|Overview of NHLBI Rare Diseases Research Activities
The National Heart, Lung, and Blood Institute (NHLBI) provides leadership for a national program in the causes, diagnosis, treatment, and prevention of diseases of the heart, blood vessels, lungs, and blood; in sleep disorders; and in the uses of blood and the management of blood resources. Through research in its own intramural laboratories and through extramural research grants and contracts, it conducts and supports an integrated program that includes basic research, clinical trials, epidemiological studies, and demonstration and education projects.
Although the major part of the research supported by the NHLBI addresses common conditions such as hypertension, coronary heart disease, and chronic obstructive pulmonary disease, a significant amount of research is devoted to rare diseases in children and adults. NHLBI activities related to rare disease research in fiscal year (FY) 2004 are described below.
Recent Scientific Advances in Rare Diseases Research
Heart and Vascular Diseases Programs
Abetalipoproteinemia is a recessive disorder of lipid metabolism characterized by the absence of apoprotein B-containing lipoproteins from the plasma. Symptoms include diarrhea, severe fat malabsorption, and acanthocytosis, a rare condition in which the majority of red blood cells have multiple spiny cytoplasmic projections. Other symptoms, including blindness and neurologic defects, all appear to be secondary to defects in the transport of vitamins A and E in the blood. The disorder is associated with abnormal processing of apolipoprotein B (apo B), which is caused by the absence of microsomal triglyceride transfer protein (MTP). Researchers in the NHLBI intramural program are studying patients with abetalipoproteinemia to document the natural history of the disorder and to look for more effective treatments. They also are conducting metabolic studies in patients with abetalipoproteinemia to clarify the role of MTP in triglyceride (fat) and fat soluble vitamin absorption. NHLBI-supported extramural researchers are actively investigating MTP’s role in the formation of apo B-containing lipoproteins. Their efforts include studies with hepatoma cells that lack MTP and that are therefore incapable of assembling or secreting apo B-containing lipoproteins. In addition, researchers have recently developed a new method for measuring MTP.
Antiphospholipid syndrome (APS) symptoms include recurrent blood clotting disorders, a history of fetal deaths, and autoimmune diseases such as thrombocytopenia. APS also increases the risk of developing atherosclerosis. Many patients with the disorder also have systemic lupus erythematosus (SLE). APS is characterized by the presence of circulating autoantibodies to certain phospholipid-binding proteins such as B2-glycoprotein I (also known as apolipoprotein H). The NHLBI supports research to determine whether genetic factors predispose individuals to develop antibodies. Researchers also are developing more standardized immunoassays for reliable detection of antibodies. In addition, investigators are studying the role of the autoantibodies in atherogenesis.
Arrhythmogenic Right Ventricular Dysplasia
Arrhythmogenic right ventricular dysplasia (ARVD) is a family of rare cardiomyopathies that result in abnormal heart rhythm and sudden cardiac death. Most forms are believed to be caused by the inheritance of autosomal dominant mutations in genes that remain largely unknown but clearly affect myocardial integrity. ARVD is characterized by marked, selective, right ventricular dilatation, myocardial cell death, and cell replacement with fat cells and fibrous tissue. Expression in gene carriers is variable but, in those who display symptoms, the disease is frequently fatal. The NHLBI supports the Multidisciplinary Study of Right Ventricular Dysplasia, an integrated network of three separate groups, to investigate genotype-phenotype relationships in familial forms of ARVD. The program uses clinical and genetic approaches to identify patients with ARVD. Study investigators are performing linkage analysis and candidate positional cloning to identify genetic regions and plausible candidate genes of interest. Two studies recently added to the Multidisciplinary Study of Right Ventricular Dysplasia should improve diagnosis and characterization of ARVD patients. An FY 2004 publication from Multidisciplinary Study of Right Ventricular Dysplasia investigators reported that (1) genetic heterogeneity exists in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), (2) mutations in the Desmoplakin gene are a relatively common cause of ARVD/C, (3) a potential genetic locus for ARVD/C is found on chromosome 8p23.2, and (4) the probable ‘final common pathway’ of ARVD/C involves cellular structures called adherens junctions. Another recent ARVD-related study from NHLBI-funded investigators reported that the high frequency of misdiagnosis of ARDV/C is due in part to over-reliance on the presence of fat and wall thinning on magnetic resonance imaging (MRI) tests and incomplete diagnostic testing. The study investigators concluded that diagnosis of ARDV/C should not rely solely on qualitative results of MRI testing.
Bartter's syndrome is characterized by salt imbalance and low blood pressure. Research on Bartter's syndrome is currently being pursued as a part of the NHLBI Specialized Centers of Research on Molecular Genetics of Hypertension. Researchers have discovered a mutation in a potassium channel that can lead to Bartter's syndrome and have demonstrated that the channel is an important regulator of blood pressure and ion and fluid balance. Mutations in chloride channels have also been identified and implicated in the development of Bartter's syndrome. Researchers think that additional Bartter's syndrome genes may exist. The hypotensive state caused by Bartter's syndrome suggests that the mutated genes may protect against the development of high blood pressure.
Beta-sitosterolemia is a rare inborn error of metabolism characterized by increased absorption of dietary cholesterol and sterols from plants and shellfish. The distinguishing feature of the disorder, a 50- to 100-fold elevation in plasma plant sterol levels, reflects both an increase in absorption of sterols from the intestine and a decrease in excretion of sterols into bile. People with beta-sitosterolemia have a markedly increased risk of premature cardiovascular disease. Effective treatment is not available at present, although a number of drugs are under development. Recent evidence suggests that sitosterolemic patients have mutations in either the ATP-binding cassette half-transporter (ABCG5) gene or in ABCG8, a similar gene that resides next to it in the genome. The phenotype resulting from deficiency of the ABCG5 protein (i.e., sitosterolemia) is identical to that caused by deficiency of ABCG8 protein, indicating that the two proteins participate in the same transport process. The profound alteration in sterol homeostasis observed in sitosterolemic patients indicates that ABCG5 and ABCG8 play a pivotal role in sterol metabolism. Researchers in the NHLBI’s intramural program are conducting molecular, cellular, and metabolic studies of beta-sitosterolemia. They are also investigating the use of a new cholesterol absorption inhibitor for the treatment of beta-sitosterolemia. Researchers funded by NHLBI extramural research grants are studying patients with sitosterolemia and other mutations of sterol absorption, basic mechanisms of sterol absorption, and related disorders of sterol metabolism.
Brugada’s syndrome, a rare inherited disorder characterized by cardiac electrophysiological abnormalities (right bundle branch block and ST elevation in the precordial leads), is associated with a high occurrence of sudden cardiac death (SCD). The condition is currently believed to be similar in cause and potential treatment to some forms of Long QT syndrome, which is caused by mutations at different locations in the SCN5A cardiac muscle sodium ion channel gene. The NHLBI supports a Program Project Grant and a small portfolio of individual research project grants to study the molecular and genetic bases of Brugada’s syndrome. NHLBI-funded investigators have shown that electrocardiographic testing, combined with the use of the sodium channel blocker ajmaline, can identify nonsymptomatic carriers of defective sodium channel genes in affected families. The complex and challenging nature of Brugada’s syndrome research was evidenced in a separate study when research on a large family with a high prevalence of SCD showed that ajmaline can sometimes provide false-positive results.
Cholesteryl Ester Storage Disease
Cholesteryl ester storage disease (CESD) is a rare syndrome characterized by an enlarged liver and spleen and abnormal liver enzymes. The disorder is known by a variety of names including lysosomal acid lipase deficiency, acid cholesteryl ester hydrolase deficiency, and Wolman disease. The severe infantile-onset Wolman disease and the milder late-onset CESD are seemingly caused by mutations in different parts of the acid lysosomal lipase gene. The mutations affect acid lysosomal lipase, an enzyme that removes lipids (cholesteryl ester and triglycerides) from lipoproteins. Acid lysosomal lipase deficiency causes a massive accumulation of lipids in tissues. The hypercholesterolemia that is common in individuals with CESD predisposes them to develop atherosclerosis. Researchers in the NHLBI’s intramural program are conducting studies to determine the role of acid lysosomal lipase in the removal of lipids from the plasma and from tissues.
Congenital Heart Defects
Congenital heart defects encompass a constellation of abnormalities in the heart that occur during embryonic development. Abnormalities of the heart are the most common of birth defects, occurring in up to 1 percent of live births, and they are an important cause of infant mortality, pediatric and adult morbidity, and shortened adult life expectancy. About one-third of affected infants and children require open heart surgery or interventional cardiac catheterization to repair or ameliorate their defects. Approximately the same proportion has associated extracardiac anomalies, such as chromosomal abnormalities and syndromes involving other organ systems.
The NHLBI has supported research in pediatric cardiovascular medicine since it first funded heart research grants in 1949. NHLBI-supported researchers have been instrumental in developing diagnostic fetal imaging techniques, surgical techniques, and medical therapies now used to ensure healthy survival for most affected children. They also have made significant contributions to the epidemiology of congenital heart defects and to understanding the molecular and genetic basis of normal and abnormal heart development. Recently, NHLBI-supported researchers have investigated the mechanism by which mutations in the Nkx2.5 gene generate conduction defects in congenital heart defects. Furthermore, they have been able to relate their work in animal models to human disease by confirming that humans with an Nkx2.5 mutation show the same defects in cardiac conduction system development as are observed in mutant mice. The NHLBI Division of Intramural Research is studying the genetics of congenital heart defects by generating new mutations in mice and then using high-frequency ultrasound to screen the offspring for congenital heart defects during the fetal period. Several gene mutations have been identified that replicate forms of congenital heart defects observed in human patients. A recipient of an NHLBI Mentored Minority Faculty Development Award showed that, in mice, embryonic stem cells can prevent cardiac malformations (that otherwise would have been caused by a genetic mutation) due to production of growth factor proteins that affect cardiac development. Further investigation of these factors may lead to new treatments to prevent or reduce the severity of congenital heart defects.
DiGeorge syndrome occurs in about 1 in 4,000 live births. The syndrome causes many abnormalities, including cardiac outflow tract anomalies, hypoplasia of the thymus and parathyroid glands, cleft palate, facial dysmorphogenesis, learning difficulties, and other neurodevelopmental deficits. It is usually sporadic, but may be inherited, and is caused by deletion of a segment of chromosome 22, which is known to contain numerous genes. The recent identification of a gene responsible for much of DiGeorge syndrome has enabled further research on how the gene is regulated and how it affects embryonic development through regulation of downstream genes. In FY 2004, researchers reported that differences in regulation of the gene in the heart, compared to its regulation in other organs affected by DiGeorge syndrome, explain why heart malformations are more common in patients than are certain craniofacial defects. The NHLBI funds grants for both human and animal studies of DiGeorge syndrome, including newly funded Specialized Centers of Clinically Oriented Research (SCCOR) in Pediatric Heart Development and Disease. Much of the NHLBI-supported basic research in congenital heart defects also enhances understanding of DiGeorge syndrome because several of the most frequent cardiac malformations occur in conjunction with the disorder.
Dysbetalipoproteinemia, or type III hyperlipidemia, is a disorder with a strong heritable component characterized by the presence of beta-migrating very low density lipoprotein (VLDL). Dysbetalipoproteinemia leads to the formation of characteristic yellow skin plaques (xanthomas) and predisposes to premature ischemic heart disease and peripheral vascular disease. The defect occurs in people with mutated forms of a protein, apoprotein E (apo E). A mutant form of apo E, apo E2, has been identified as the chief molecular defect. Animal models have been developed to facilitate basic research on this disease. Mice expressing human apo E2 show increased plasma cholesterol and triglyceride levels. Similar increases in lipid levels are seen in humans with type III hyperlipidemia. Hyperlipidemia can be ameliorated in the mice by increasing expression of the low-density lipoprotein receptor by two-fold. The NHLBI Division of Intramural Research is investigating the relationship between mutant apo E and the development of dysbetalipoproteinemia. Intramural researchers are studying patients with the disease to define its natural history and develop better treatments.
Familial hypobetalipoproteinemia (FHBL) is a disorder of lipid metabolism characterized by greatly reduced levels of apoprotein B (apo B)-containing lipoprotein cholesterol. Several different types of FHBL have been found, each resulting from a different mutation. Scientists estimate that fatty livers (which have a five-fold increase in fat compared to normal livers) may be present in up to 80 percent of people with a form of FHBL resulting from apo B truncation. Individuals with the most severe form of the disease develop defects in the transport of vitamins A and E in the blood, resulting in blindness and neurologic defects. In one group of patients with FHBL, a gene mutation on chromosome 2 has been identified and characterized. The mutation results in truncation of apo B. Another group of eight families has been identified that appear to have a different form of FHBL with involvement of a different region of chromosome 2. A genome-wide search suggests another candidate gene on chromosome 3. Mechanistic studies infer that the fatty livers found in patients with apo B-defective FHBL are caused by an inability of the liver to export triglyceride. The NHLBI intramural program is investigating the role of apo B and other factors in the development of FHBL. Intramural researchers are studying patients with FHBL to clarify the natural history of the disorder and to look for more effective treatments. They also are performing metabolic studies in patients to clarify the role of apo B and other agents that might cause defects in absorption of triglycerides (fat) and fat soluble vitamins. The NHLBI extramural program funds research grants to study genetic, biochemical, and metabolic aspects of FHBL.
Homozygous Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevated concentrations of low-density lipoproteins (LDL). The homozygous form of FH is rare (one in a million), but people who have it are very prone to premature coronary heart disease.
Cholesterol derived from LDL, when deposited in arteries, leads to heart attacks and, when deposited in tendons and skin, causes xanthomas. FH is caused by a mutation in a gene specifying the receptor for plasma LDL. LDL receptors facilitate the removal of LDL. When they are deficient or absent, the rate of LDL removal declines, causing the level of LDL in the plasma to rise. The NHLBI Division of Intramural Research is investigating the role of the LDL receptor in FH. Patients in intramural studies are eligible to undergo serial testing that includes noninvasive cardiac monitoring and measurement of biomarkers. The goal of the studies is to document the natural history of FH and the development of atherosclerosis. Recently, intramural researchers have made progress in the use of MRI for noninvasive evaluation of the development of aortic root atherosclerosis in patients with familial hypercholesterolemia. In the NHLBI extramural program, several grants support studies on the biochemistry, genetics, and potential treatment of the disease.
Lecithin Cholesterol Acyltransferase Deficiency
Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare syndrome characterized by cloudy cornea, kidney failure, and extremely low levels of high-density lipoprotein (HDL). The disorder is inherited on chromosome 16 and is caused by a lack of the enzyme LCAT, which aids in the formation of normal HDL. Researchers in the NHLBI’s intramural program are investigating molecular, cellular, and metabolic defects associated with human LCAT and their role in LCAT deficiency. Patients with LCAT deficiency are being studied to clarify the natural history of the disorder and to develop better treatments. Intramural researchers are also performing studies in patients to determine the role of LCAT in HDL formation and in the development of atherosclerosis.
Lipoprotein Lipase Deficiency
Lipoprotein lipase deficiency (LPL) is a rare genetic lipid disorder characterized by extremely elevated triglyceride (fat). It is caused by a genetic defect that affects an enzyme involved in breaking down triglyceride (fat) and removing it from the blood. The specific gene defect, which is found on chromosome 8, is in the enzyme LPL gene. The excess triglycerides characteristic of the disorder are often deposited in the skin (eruptive xanthomas), back of the eye (lipemia retinalis), liver, and spleen and cause abdominal pain or pancreatitis in children. Researchers in the NHLBI intramural research program are conducting metabolic studies in patients with LPL deficiency to determine the role of the lipases in the metabolism of triglyceride lipoproteins and in the development of atherosclerosis and pancreatitis.
Klippel-Trenaunay-Weber syndrome (KTWS) is a very rare, vascular deformation disease of unknown incidence, involving capillary, lymphatic, and venous channels. It usually manifests itself as three symptoms: cutaneous port-wine capillary malformations, varicose veins, and enlargement of soft tissues and bone in one limb. KTWS symptoms are usually present at birth, with 75 percent of patients having symptoms before the age of 10. One NHLBI grant supports molecular research on characterizing the gene(s) responsible for KTWS.
Recently, researchers found a de novo supernumerary small ring marker chromosome derived from chromosome 18 in a patient with Klippel-Trenaunay syndrome, the first demonstration of such an extra chromosome in a patient with KTWS. The finding is unique for a rare vascular-overgrowth syndrome and may help researchers to define candidate genes for this disorder.
Liddle's Syndrome is a rare autosomal dominant disorder of severe hypertension characterized by increased renal reabsorption of sodium resulting in hypokalemia, low plasma renin activity, and hypoaldosteronism. Liddle's Syndrome is ameliorated by amiloride, a drug that blocks sodium reabsorption and potassium excretion. Studies have shown that a mutation in the gene encoding the beta-subunit of the epithelial sodium channel in the distal renal tubule is responsible for this disorder. A diagnostic test for Liddle Syndrome is being developed by one of the NHLBI Specialized Centers of Research Programs on the Molecular Genetics of Hypertension.
Long QT Syndrome
Long QT syndrome (LQTS) is characterized by a prolonged QT segment on an electrocardiograph and is associated with fainting (syncope), ventricular arrhythmias, and, frequently, sudden cardiac death. LQTS comprises a family of related diseases that are often inherited and that are repolarization induced by mutations in cardiac ion channel genes. In some forms of the disease, affected individuals may inherit other abnormalities, such as deafness, and have varied clinical outcomes depending on their specific mutational patterns. About 70 percent of diagnosed cases are in women. Recently, three specific gene mutations have been identified (KvLQT1, HERG, and SCN5A), which are associated with three forms of LQTS (LQT1, LQT2, and LQT3). The NHLBI currently supports research on LQTS through a Specialized Center of Research on Sudden Cardiac Death and through many other grants that address the molecular, clinical, and genetic bases of this condition. The NHLBI also supports an investigator-initiated grant comprising an international LQTS registry with over 1,000 families. It includes 2,235 affected individuals; 1,275 family members with borderline LQTS; and 2,429 unaffected family members. Investigators are continuing genetic investigations to identify known genetic variants in registry members and to identify new variants and mutations. LQTS researchers also are assessing genotype-phenotype correlations as well as the long-term course of the disease by evaluating triggering factors for malignant ventricular arrhythmias.
Several recent advances in LQTS research will help guide the clinical care of LQTS patients. Some recent findings are that (1) age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients (2) LQT2 patients with mutations in the pore region of the HERG gene are at increased risk of arrhythmic events compared to those whose mutations are in the nonpore regions (3) exercise triggers adverse events in LQT1 patients, whereas most events in LQT2 and LQT3 patients occur during rest or sleep (4) unexpectedly common mutations in five of the genes responsible for cardiac potassium and sodium ion channel regulation are related to the expression of congenital LQTS in certain families, and (5) individuals with atypical LQTS have a defective gene coding for production of a defective cardiac cell structural protein believed to cause sodium, potassium, and calcium imbalances; unusually long QT intervals; arrhythmias; and sudden death. In addition, studies of nervous system involvement in LQTS have led to new types of successful surgical management of high-risk patients and to a new oral therapy for one type of LQTS.
Marfan syndrome is an inherited connective tissue disorder associated with cardiovascular complications such as aortic aneurysms (which are potentially fatal) and mitral valve prolapse as well as noncardiac complications such as dislocation of the eye lens. The disease occurs in about 1 per 10,000 persons and in all races. The NHLBI supports animal research on the assembly of microfibrils and their effects on cardiovascular development as well as on aortic aneurysm development and its treatment in the atherosclerotic population. The research may have implications for treating aneurysms in people with Marfan syndrome.
The NHLBI plans to support a data coordinating center to develop and maintain a registry of patients with Marfan syndrome and other connective tissue diseases who receive treatment for cardiovascular complications and to enable research to determine best medical practices for advancing awareness and clinical management of genetic thoracic aortic aneurysms and other cardiovascular complications. The registry will: (1) collect information on patients, care providers, hospitals, and clinical interventions; (2) collect blood and tissue specimens; and (3) maintain a repository of tissue and blood, family pedigrees, and data on extra-cardiac complications. The NHLBI will collaborate with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Eye Institute (NEI), the National Institute of Dental and Craniofacial Research (NIDCR), and the National Human Genome Research Institute (NHGRI) in facilitating standardized reporting by the registry of patient characteristics, indications for surgical intervention and other treatments, and adverse events. The National Marfan Foundation, which participated in a 2002 NHLBI-sponsored working group on this disorder, is fully supportive of the registry and intends to encourage participation from its membership.
Niemann-Pick Type C Disease
There are several types of Niemann-Pick (NP) disease: types A (NPA), B (NPB), C (NPC), and D (NPD). NPC disease is a lipid storage disorder usually characterized by excessive accumulation of cholesterol in the liver, spleen, and other vital organs. Affected individuals have cardiovascular disease, enlargement of the liver and spleen (hepatosplenomegaly), and severe progressive neurological dysfunction. The gene deficiency in NP disease types A and B affects sphingomyelinase, an enzyme that breaks down the lipid sphingomyelin. The gene deficiency in NP disease types C and D affects the NPC-1 protein whose function remains obscure. Animal studies and basic research show that mutations in NPC-1 interfere with lipid metabolism, cholesterol homeostasis, and intracellular cholesterol trafficking. Although the dysfunctions cause severe damage to the nervous system, bone marrow, and other tissues and organs in people with NPC, they also appear to stabilize atherosclerotic plaques against rupture and may thus protect adults who carry the NPC mutation from cardiovascular events such as heart attack, angina, and stroke. The defect in intracellular cholesterol movement leads to abnormal accumulation of cholesterol in a cellular compartment called the lysosome.
The NHLBI funds grants for research on regulation of intracellular cholesterol movement that leads to lipid accumulation in NPC disease.
Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder caused by a defect in an enzyme active in the last step of cholesterol biosynthesis. As a result of the defect, endogenous cholesterol synthesis is inadequate for meeting biological demands for functions such as membrane structure and bile acid synthesis. The disorder also leads to accumulation of the cholesterol precursor 7-dehydrocholesterol and its derivatives. Newborns with SLOS have a distinctive facial dysmorphism; suffer from multiple congenital anomalies including cleft palate, congenital heart disease, genitourinary abnormalities, and malformed limbs; and exhibit digestive difficulties, severe developmental delays, and behavioral problems. Scientists now think that SLOS could be the cause of many previously unexplained cases of mental retardation. During FY 2004, the NHLBI supported two investigator-initiated grants on SLOS. One investigator is using transgenic animal models of SLOS to study the basic pathophysiology of the condition, to develop improved molecular therapeutic approaches, and to increase understanding of the normal role of cholesterol in fetal development. The other researcher is investigating sterol balance and lipid metabolism in infants with SLOS, the effectiveness of cholesterol-supplemented baby formula in ameliorating some of the behavioral and digestive symptoms of SLOS, and the effectiveness of simvastatin therapy in lowering the plasma concentrations of toxic forms of abnormal cholesterol precursor compounds. In FY 2004, investigators reported that providing additional dietary cholesterol as egg yolk to SLO infants successfully raises plasma lipid levels in favorable ways. The functional implications of the finding are not yet clear because certain measures of developmental progress do not appear to change in response to dietary cholesterol. Therefore, the interesting findings do not yet form a basis for altering clinical management for children with SLOS. Future research activities will explore the effects of different types of dietary manipulations in detail.
Supravalvular Aortic Stenosis
Supravalvular aortic stenosis (SVAS) is a vascular proliferative obstructive disease that affects the aorta and the coronary, carotid, and peripheral arteries. The incidence of SVAS is thought to be less than 5 percent of all congenital heart defects. Researchers think that SVAS is caused by a mutation in the gene for elastin, an extracellular matrix protein accounting for about 50 percent of the dry weight of the vascular wall. Recent studies suggest that native elastin maintains the contractile phenotype of vascular smooth muscle cells. The mutation in elastin found in individuals with SVAS activates genes that contribute to a change in the phenotype of vascular smooth muscle cells from a contractile nonmigratory state to noncontractile, migratory, proliferating state. The NHLBI supports three grants focused on SVAS.
Tangier disease is a rare syndrome characterized by a deficiency of high-density lipoprotein (HDL), mild hypertriglyceridemia, neurologic abnormalities, and massive cholesterol ester deposits in various tissues such as the tonsils.
The disease is inherited and appears to be caused by excessive breakdown of HDL rather than by a fault in HDL synthesis. Tangier disease patients have defective intracellular lipid trafficking that prevents removal of cholesterol from cells. A member of the ATP-binding cassette (ABC) transporter family (human ABCA1) located on chromosome 9 has been identified as the defective gene in Tangier disease. ABCA1 is thought to be the gatekeeper for eliminating excess cholesterol from tissues and, therefore, key in determining cholesterol accumulation in arterial walls. Researchers in the NHLBI’s intramural program are studying patients with Tangier disease to clarify its natural history. Their research has shown an intracellular role for ABCA1 in the removal of cholesterol from peripheral cells. They also have shown that ABCA1 is involved in the formation of HDL particles from the liver. Metabolic studies performed by intramural researchers are helping to expand understanding of the role of the different HDL particles in the removal of cholesterol from the body. The NHLBI also funds extramural research grants to investigate the cell biology and biochemistry of human ABCA1 and its role in Tangier disease. Recent research efforts have been directed at understanding the critical regions in apo AI necessary for ABCA1-mediated lipid efflux. Families with low HDL who have new variants of ABCA1 have been identified and the functional significance of their variants is being examined.
Trimethylaminuria (TMAU) is caused, most often, by genetic mutations that inactivate specific liver enzymes, leading to defects in the body’s ability to break down trimethylamines (TMAs). TMAs are volatile compounds that are produced by the action of gastrointestinal bacteria on choline and related substances derived from the diet. TMAU occasionally occurs with some liver and kidney diseases and with other genetic syndromes such as Prader-Willi syndrome. In people with TMAU, excess TMA is excreted in sweat and exhaled into the air causing offensive odors that lead to severe social isolation. Some patients experience constant symptoms and others have fluctuations in the intensity of odors. Neurologic and psychiatric symptoms, such as seizures and depression, may also be present. Most cases are diagnosed in adults, although onset in childhood can occur. Diagnosis is difficult and compromised by social stigma. Case reports suggest that symptoms in many TMAU patients can be ameliorated by diets low in choline, lecithin, carnitine, lysine, other dietary amines, and vegetables from the cabbage family.
Lung Diseases Programs
Advanced Sleep Phase Syndrome
Advanced sleep phase syndrome (ASPS) is a rare, genetically based sleep disorder characterized by an early evening onset of sleep, normal sleep duration, and spontaneous early awakening. The disorder leads to insomnia, excessive daytime sleepiness, and impairment of daily functioning and quality of life. The NHLBI supports basic research to elucidate the neural pathways through which the biological clock mechanism regulates sleep, clinical research to elucidate genetic risk factors, and applied research to determine the role of the biological clock in disturbed sleep and alertness of shift workers, school-age children, and drowsy drivers.
Alpha-1 Antitrypsin Deficiency
Alpha-1-antitrypsin (AAT) deficiency is an inherited deficiency of a circulating protein inhibitor that is manufactured primarily in the liver. The deficiency is associated with emphysema, presumably due to inadequate protection against enzymatic destruction of lung elastic fibers by neutrophil elastase. Fifteen percent of the AAT-deficient population also develops liver disease. The NHLBI funds clinical and basic research on AAT deficiency, including studies of the molecular mechanisms that impair AAT secretion, methods of gene therapy delivery, and methods to increase the availability of defective, but partially active, AAT. NHLBI-supported investigators are defining the abnormalities and degradation pathways of the AAT protein, characterizing the inflammation that leads to disease in various AAT deficiency states, and evaluating the possibility of treating the disease with drugs that would enhance the release of partially active mutant protein from liver cells. The objective of one genetic study of families is to identify other genes that may modify the nature and severity of the disease in different individuals. A gene therapy clinical trial is testing whether the AAT protein is produced in skeletal muscle cells after injection of a viral vector construct that includes the AAT gene. In addition to research that specifically focuses on AAT, the NHLBI supports related studies addressing lung transplantation; the general causation of emphysema; the function, synthesis, secretion, and interaction of the enzymes that are inhibited by AAT; animal models of other enzyme inhibitor deficiencies; gene regulation; cellular signaling, injury, and repair; and protein processing.
Asbestosis, an occupational lung disease, is characterized by interstitial pneumonitis and fibrosis resulting from exposure to inhaled asbestos fibers. In response to the deposition of asbestos fibers, macrophages and lymphocytes accumulate, type II alveolar epithelial cells and smooth muscle cells proliferate, fibrosis appears in the adjacent walls of respiratory airways, and the alveolar septa thicken. Furthermore, asbestos fibers can be associated with cell transformation and proliferation related to lung cancers. NHLBI-supported researchers are investigating the molecular and cellular events that trigger cellular proliferation in and regulate remodeling of lung tissue, which results in fibrotic lesions and, perhaps, in malignant cell changes in response to asbestos. Recent advances in research related to asbestosis may help to explain why certain kinds of asbestos exposure (crocidolite) are associated with cancers. In experiments using epithelial cells, researchers recently showed that crocidolite asbestos depletes the intracellular antioxidant glutathione, causing increased production of an enzyme (gamma-glutamylcysteine synthetase) that increases levels of a cancer causing proto-oncogene. Another study showed that after exposure to asbestos, Type II lung epithelial cells activate extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are stimuli for cellular proliferation.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by disordered lung growth, changes in lung cell size and shape, and a reduction in the number of alveoli available for gas exchange. The NHLBI program in developmental lung biology supports basic and clinical research to increase understanding of BPD and identify treatment opportunities.
The Collaborative Program for Research in BPD provides a well-characterized primate model of BPD for a multi-disciplinary exploration of the molecular mechanisms involved in the etiology of BPD. One of the participating Centers of the NHLBI’s SCOR Program in Pathobiology of Lung Development has identified nitric oxide (NO) as an important regulator of pulmonary circulation during development. The centers are conducting two clinical trials on the role of NO in preventing and treating chronic lung disease in premature infants. Together, the clinical studies are expected to yield definitive information about the utility and window of therapeutic opportunity for prevention of chronic lung disease with inhaled NO in very low-birth-weight premature infants. In addition, in FY 2004, the NHLBI entered into a funding collaboration with the National Institute of Child Health and Human Development to conduct a prospective, randomized study to test the individual factors of lower and conventional oxygen levels and two ventilatory strategies [conventional and nasal continuous positive airway pressure (nCPAP)] in very low-birth-weight, premature infants. The results of the study could exert broad influence on the clinical management of very low-birth-weight premature infants.
Several recent research advances may help scientists to discover new treatments for BPD. One study demonstrated a reduction of ventilatory injury with nCPAP in a preterm baboon model of BPD. In another study, a histological exam showed that baboon infants receiving nCPAP in place of conventional ventilation had more normal appearing, thinner, septated alveoli with associated capillary beds, although the absolute number of alveoli remained decreased compared to gestational age controls. Other recent work has shown that anti-bombesin antibody A211 promotes the growth of capillaries into developing alveolar septae, increasing the extent of alveolization in the 21-day baboon BPD model. Finally, analysis of the role of airway serpin (an antiproteinase) in balancing the activities of proteinases-antiproteinases during lung development reveals that proteinases are upregulated in BPD, whereas their local inhibitors are either downregulated or unchanged.
Congenital Central Hypoventilation Syndrome
Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by normal breathing while awake but shallow breathing during sleep (hypopnea) that is not effective in moving fresh air into the lungs. In severe cases, breathing is also ineffective in affected individuals who are awake. The NHLBI supports a basic research program to elucidate the anatomical and physiological factors responsible for generating neural rhythm and translating it into breathing. Research is focused on understanding how breathing is regulated and identifying the conditions under which reflexive generation of respiratory rhythm is suppressed. Identification of the neuronal pathways producing respiratory rhythm and pattern is a prerequisite for a full understanding of a variety of respiratory sleep disorders such as CCHS. Genetic and pathology studies of CCHS patients are now leading to identification of candidate genes and of specific areas of the brain stem involved in autonomic regulation including respiration.
Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia (CDH) is a developmental disorder that occurs once in every 2,400 births. Often CDH occurs in isolated fashion, i.e., it is not associated with any other life-threatening anomalies or chromosomal aberrations.
Without surgical intervention neonates die soon after birth because their lung tissue, compressed by their herniated viscera, is inadequately developed. In infants with CDH, hypoplasia of the lung and its vascular bed leads to pulmonary hypertension or persistent fetal circulation syndrome. Recently, an investigator-initiated study funded by the NHLBI proposed to test the efficacy of an in utero surgical technique to correct lung hypoplasia in human fetuses with the most severe form of congenital hypoplasia. Enrollment was terminated on July 17, 2001, because of the unexpectedly high survival rate with standard care (postnatal surgery). The researchers determined that further recruitment would not result in significant differences between the standard care group and the in utero surgical group. Their findings of no difference in mortality, morbidity, and lung function between the two groups were published in the New England Journal of Medicine in FY 2004. The report was based on the results from 24 infants randomized before the study was terminated.
Cystic fibrosis (CF) is a multi-system disease affecting a variety of epithelial tissues, characterized by defective transport of chloride and sodium across cell membranes. More than 25,000 Americans have CF, with an incidence of about 1 in 3,300 among Caucasians, making CF the nation’s number one genetic cause of death for children and young adults. Defects in a single gene, the CF transmembrane conductance regulator (CFTR) gene, give rise to the disorder. The mutations in CFTR lead to abnormal secretions, recurrent infection and inflammation, bronchiectasis, and premature death. Lung disease is the major cause of morbidity and mortality in people with CF. Increasing evidence suggests that defects in the CTFR gene do not function alone in determining disease outcome. The severity of pulmonary disease can vary greatly among individuals, even in those with identical CTFR mutations. Evidence suggests that the variation is due to the interaction of the defects in the CTFR gene with other genes that can affect the final disease presentation.
The NHLBI supports a program of basic, clinical, and behavioral research in CF focused on the causes, pathophysiology, and treatment, specifically as it relates to the pulmonary manifestations. Four investigator-initiated program project grants in the area of gene therapy for CF were awarded in FY 2004. The grants are focused on developing improved vector delivery systems and overcoming barriers to gene therapy. In FY 2004, the NHLBI, in partnership with the National Institute of Diabetes and Digestive and Kidney Diseases, the Cystic Fibrosis Foundation (CFF), and several companies, sponsored an investigator-initiated multi-center clinical trial, Early Antipseudomonal Therapy in Cystic Fibrosis. It is the largest clinical trial involving young children with CF ever to be conducted in the United States and would be impractical without the Therapeutics Development Network (TDN) infrastructure, a unique resource for the CF research community, funded by the CFF and the NIH National Center for Research Resources (NCRR). The trial is seeking to determine the best treatment for initial Pseudomonas infection to delay or prevent chronic infections that lead to irreversible lung destruction and eventual death.
Two recent scientific advances have increased understanding of CF. For the first time, investigators have demonstrated that airway hydration plays a critical role in lung defense. Their results predict that rehydrating airway surfaces will be an effective form of therapy for CF and, perhaps, for chronic bronchitis and some forms of asthma as well. In their experiments, overexpression of an epithelial sodium channel in mice caused accelerated sodium transport and initiated CF-like airway disease but did not affect chloride secretion, suggesting that an imbalance of sodium absorption and chloride secretion can produce CF-like disease. In another study, researchers focused on excess mucus production and secretion, a well-recognized feature of inflammatory respiratory diseases such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease. They discovered a key protein in the mucin secretory process (called MARCKS for myristolyated alanine-rich C kinase substrate) that regulates mucus secretion. When a peptide fragment from the protein, dubbed MANS, was created and tested in an animal model of disease, it sharply reduced or in some cases eliminated the excess mucin secretion, preventing the airways from clogging. The innovative findings lay a foundation for new therapies for a spectrum of respiratory diseases characterized by mucus hypersecretion.
Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, lung disease in which functioning normal lung tissue is replaced by nonfunctional connective (scar) tissue, which contains fibroblasts, myofibroblasts, and collagen. The causes of IPF are unknown, but the disease is commonly treated with corticosteroids, sometimes in combination with other immunosuppressant drugs, and less commonly with lung transplantation. Individuals with pulmonary fibrosis develop abnormal, excessive scarring that can cause progressive shortness of breath and cough. Therapy is rarely effective and the disease progresses, resulting in death over a relatively short time in most patients. NHLBI intramural researchers are conducting studies focusing on the natural history and pathogenesis of pulmonary fibrosis. Four intramural NHLBI observational clinical research protocols are enrolling individuals with pulmonary fibrosis. NHLBI-supported extramural researchers are investigating the molecular and cellular events that trigger the alveolar injury seen in early stage idiopathic pulmonary fibrosis that initiates progression to an irreversible, fibrotic end stage of the disease.
New research shows that fibroblasts involved in tissue fibrosis, which were previously believed to originate locally in lung tissue, originate in the bone marrow as progenitor fibroblasts. The finding, which indicates that local lung tissue injury can lead to a systemic response, has introduced new possibilities for treatment of IPF. Other recent scientific advances related to IPF include the discovery that a number of cytokines that cause fibroblasts to become activated and to proliferate are involved in the development of the disease. A great deal of research has focused on the transition of activated fibroblasts into myofibroblasts, which produce the growth factor TGF beta, a primary cause of dysregulated tissue repair. Recent research showed that the shift from activated fibroblast to myofibroblast is related to the presence of prostaglandins. Currently, TGF beta-secreting myofibroblasts are being targeted using immunosuppressant (interferon gamma) therapy. The treatment, which has been given to patients with newly diagnosed IPF, has produced modest improvement in younger patients with less severe disease. In another study, a murine model made deficient in leukotrienes was protected against fibrosis. A similar approach is being evaluated in IPF patients who are receiving an anti-leukotriene drug (Zileuton).
Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects women, usually during their reproductive years. Symptoms develop as a result of proliferation of atypical, nonmalignant, smooth muscle-like cells (LAM cells) in the lungs and in abdominal tumors (angiomyolipomas, lymphangioleiomyomas). Common symptoms include shortness of breath, cough, and sometimes coughing up blood. Patients often develop spontaneous pneumothorax or chylous pleural effusion (collapse of the lung or collection of milky looking fluid around the lung). The clinical course of LAM is quite variable but is usually slowly progressive, eventually resulting in death from respiratory failure. Although no treatment has been proven effective in halting or reversing LAM, lung transplantation is a valuable treatment for patients with end-stage lung disease. More than 30 percent of patients with tuberous sclerosis complex (TSC) develop lung lesions identical to those seen in LAM. The underlying genetic mechanisms leading to smooth muscle proliferation in LAM and TSC are controlled by abnormalities in the same genes, but TSC is inherited and LAM is a disease that occurs sporadically (does not appear to run in families).
As part of its intramural program, the Institute has established a research laboratory at the NIH Clinical Center to learn more about the cause and progression of LAM. Intramural researchers have been studying bone mineral density (BMD) in LAM patients, because LAM is frequently treated with anti-estrogen therapy (e.g., oophorectomy, progesterone), which can cause BMD loss. The researchers found that abnormal BMD, observed in roughly 70 percent of patients, was correlated with the severity of lung disease and with age. Greater severity of lung disease and oophorectomy therapy were associated with loss of BMD. Similar rates of decline in BMD were found in progesterone-treated and untreated patients. However, bisphosphonate-treated patients had lower rates of decline in BMD than did untreated patients. Based on these observations, the investigators recommended systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.
The NHLBI extramural program supports a national LAM Patient Registry, co-funded by the Office of Research on Women’s Health and coordinated by the Cleveland Clinic Foundation. The LAM Registry began enrolling patients in the summer of 1998. Enrollment closed in September 2001 with 243 patients recruited. The NHLBI LAM Registry program is continuing to help manage the collection, processing, and distribution of LAM tissue for current LAM projects as well as a repository of LAM tissue for future research. A recent study of blood vessels cells in benign angiomyolipomas in LAM patients showed that the vascular cells in these tumors are neoplastic. In addition, scientists recently showed for the first time that estrogen stimulates the growth of LAM-like cells from angioleiomyomas (benign kidney tumors). This may help to explain why LAM is almost exclusively a disease of women.
Narcolepsy is a disabling sleep disorder affecting over 100,000 people in the United States. It causes excessive daytime sleepiness and rapid onset of deep (REM) sleep. Other symptoms include abnormalities of dreaming sleep, such as dream-like hallucinations and transient periods of physical weakness or paralysis (cataplexy). Low cerebrospinal fluid levels of hypocretin, a neurochemical messenger linking sleep with the regulation of muscle tone and alertness, are highly specific to narcolepsy. The NHLBI supports basic and clinical research to identify brain abnormalities associated with narcolepsy that contribute to symptoms such as daytime sleepiness, sleep disturbance, and physical weakness.
Persistent Pulmonary Hypertension of the Newborn
Persistent pulmonary hypertension of the newborn (PPHN) affects approximately 1 in 1,250 live-born term infants. Due to inappropriate muscularization of fetal pulmonary vessels, the lung arteries of affected newborns fail to dilate after birth to allow for normal blood flow through the lung. Infants with PPHN are poorly oxygenated and require costly and prolonged medical care including intubation of the airway, inhalation of 100-percent oxygen, mechanical ventilation and, often, heart/lung bypass (extracorporeal membrane oxygenation). The NHLBI supports a spectrum of basic and clinical research grants concerned with achieving a mechanistic understanding of structural and functional defects of the pulmonary circulation in order to create new opportunities for correcting them. One of four NHLBI-funded Specialized Centers of Research on the Pathobiology of Lung Development is studying several aspects of the unique vascular response of the neonate to injurious stimuli to identify basic molecular mechanisms involved in the development of hypertensive pulmonary disorders such as PPHN.
Several recent advances have been made in research related to PPHN. Recent clinical studies point to a critical role for endogenous nitric oxide as a modulator of levels of vasoactive mediators whose net balance determines pulmonary vascular tone and reactivity. New basic research studies indicate that a subpopulation of circulating monocytes (a type of white blood cell) are recruited to the pulmonary vasculature and contribute significantly to the accumulation of Type I collagen in the hypertensive vessel wall. Evidence is accumulating that at least some of these circulating progenitor cells differentiate into cells expressing a myofibroblast-like phenotype. Researchers have suggested that at least some forms of PPHN may result from abnormal accumulation of circulating pluripotent cells within the vessel wall. Thus, rational treatment of the disease depends on a mechanistic understanding of the fibroblast proliferative response observed in PPHN and may need to include therapies to inhibit the recruitment of fibroblasts to the vessel wall. In another recent clinical study, NHLBI-funded researchers performed a rigorous analysis of the data related to maternal risk factors for PPHN. Their analysis failed to support previously reported risk factors, such as smoking, while identifying some previously unrecognized risk factors. For example, third-trimester exposure to selective serotonin reuptake inhibitors (SSI) was associated with a two-fold increase in risk for BPD, whereas a 50-percent reduction in risk was associated with third-trimester exposure to ibuprofen. A six-fold increase in risk for PPHN was associated with C-section.
Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD), also known as Kartegener’s syndrome or immobile ciliary syndrome, is an inherited disease characterized by defects in the cilia lining the respiratory tract. Patients with PCD exhibit impaired ciliary function, reduced or absent mucous clearance, and susceptibility to chronic, recurrent respiratory infections, including sinusitis, bronchitis, pneumonia, and otitis media. The disease typically affects children ages 0 to 18 years, but the defect associated with it has a variable clinical effect on disease progression in adults as well. Many patients experience hearing loss and, in males, infertility is common. Another symptom, situs inversus (having organs on the opposite side from usual), occurs in approximately 50 percent of PCD patients. Clinical progression of the disease is variable, with lung transplantation required in severe cases. For most patients, aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections are recommended. NHLBI-supported researchers are relating the molecular etiology of PCD to the ciliary phenotype. A large cohort of subjects with PCD is undergoing rigorous diagnostic evaluation and determination of the specific ultrastructural abnormalities in their cilia. The relationship of mutations in specific genes to ultrastructural defects and ciliary functions is being investigated.
In a recent study, researchers evaluated diagnostic and phenotypic features in a large cohort of PCD patients to identify the major clinical and biologic markers of disease and to enable the categorization and characterization of patients. A combination of a careful clinical history and an examination of ciliary structural analysis and measures of biologic markers such as nasal nitric oxide was found to be useful in the diagnosis of PCD. Two other recent studies suggest that ciliated cells may have unique functions besides sweeping the airways; specifically, ciliated cells also appear to be equipped with specialized tools for transport and signaling. A regulatory factor (Foxj1), initially identified for its role in ciliogenesis in epithelial cells, has been shown to modulate immune lymphocyte differentiation, immune tolerance, and inflammation. A similar role for the regulatory factor in the airway epithelium would have profound implications since airway inflammation is important in lung disease. Finally, recent NHLBI-supported studies found that cell-associated enzymes from patients with PCD and other chronic lung diseases enhance nucleotide metabolism on airway epithelial cell surfaces. Enhancement of nucleotide metabolism could represent a protective mechanism against the deleterious effects of excess amounts of the nucleotide ATP. However, enhanced nucleotide metabolism and clearance also may exaggerate chronic inflammation in patients with PCD.
Primary Pulmonary Hypertension
Primary pulmonary hypertension (PPH) is a rare condition characterized by structural changes in small pulmonary arteries that lead to increased resistance to blood flow in the lungs and to heart failure. Over the past 25 years, PPH has been transformed from a poorly described disease with a dire prognosis to a well-defined illness that is being studied in basic investigations and clinical trials. Treatment with agents such as prostacyclins has improved the prognosis and quality of life of PPH patients, and newer treatment options such as endothelin inhibitors have recently become available. Despite recent advances, treatment is expensive and can have troublesome side effects. An important current priority is accelerating the translation of basic research advances into better therapies. The NHLBI supports research to identify the causes of PPH initiation and progression. Currently, the development of PPH is thought to require a genetic susceptibility followed by one or several secondary trigger factors such as viral infection or drug exposure. Determinants of genetic susceptibility and interaction of genotype with promoting or modifying factors are areas of active research. Other work is exploring the pathways within lung cells that contribute to the symptoms and pathology of PPH and the mechanisms underlying the abnormal proliferation of vascular cells in patients with PPH.
The discovery that a mutation in bone morphogenetic protein receptor 2 (BMPR2) is a genetic cause of PPH has sparked research on pathogenesis and therapeutic targets. Rapid progress is being made in the search for a trigger or modifying condition for clinical presentation of BMPR2 mutations. The NHLBI supports a PPH Family Registry that was begun in 1994 to discover the genetic mechanism(s) of the disease. The registry currently comprises 81 families and has collected 324 samples for study. Research is determining whether variations in certain candidate genes contribute to development of the disease in genetically susceptible individuals. Current data from the registry suggest that roughly 50 percent of familial and 26 percent of nonfamilial (sporadic) PPH patients have mutations in the coding region of the BMPR2 receptor gene. As only 20 percent of individuals with a BMPR2 mutation develop PPH, other genetic factors likely play a role. Recent findings from the registry identified several possible modifier genes, including serotonin transporter, nitric oxide synthase 3, and vasoactive intestinal peptide, that may be risk factors for development of clinical disease or may in part determine the age of disease onset. Elucidating the genetic basis of PPH will enhance the ability of clinicians to inform affected family members about their risk of developing the disease. The basic research already funded by the NHLBI has enabled development of new agents that are currently being evaluated in clinical trials. So it is reasonable to expect that further basic research advances will lead to better treatments for PPH and other forms of severe pulmonary arterial hypertension.
Sarcoidosis is a disease involving organ systems throughout the body in which normal tissue is invaded by pockets of inflammatory cells called granuloma. Most sarcoidosis patients have granuloma in their lungs. The disease can occur in a mild form that disappears spontaneously or in a severe form that results in a life-long condition. Estimates of the number of Americans with sarcoidosis range from 13,000 to 134,000, and between 2,600 and 27,000 new cases appear each year. Up to 5 percent of individuals with pulmonary sarcoidosis die of causes directly related to the disease. The morbidity associated with sarcoidosis can be severe, resulting in significant loss of function and decrease in quality of life. The causes of sarcoidosis are presently unknown, but disease development is thought to involve both a genetic predisposition and the immune system. Although corticosteroids are the mainstay of current treatment, alternative therapies could be beneficial given the multiple side effects that can arise from the use of corticosteroids.
The NHLBI supports research on sarcoidosis in both its extramural and intramural programs. Researchers in the NHLBI’s intramural laboratories conduct translational studies relating to the effectiveness of cyclic nucleotide phoshodiesterase inhibitors and statins as potential new therapies for sarcoidosis. The NHLBI also funds extramural research grants to investigate the causes of sarcoidosis and the role of immune cell responses in the disease. As part of its extramural program, the NHLBI also supports a multicenter study, the U.S. Sarcoidosis Genetic Analysis Consortium (SAGA), to perform linkage analysis of 360 African-American families with affected siblings, using a 300-microsatellite marker scan. The focus is on African Americans as they are more likely to report a family history of sarcoidosis, present at an earlier age, and have more severe disease.
The NHLBI multi-center ACCESS (A Case Control Etiologic Study of Sarcoidosis) study created a repository of DNA specimens collected from more than 700 sarcoidosis patients and paired controls. A public access database for the repository is being prepared. In FY 2004, a publication by ACCESS investigators reported on social predictors of disease severity at presentation. The results showed that lower income, the absence of private or Medicare health insurance, and other barriers to care were associated with sarcoidosis severity at presentation, as were race, sex, and age. Blacks were more likely to have severe disease by objective measures, while women were more likely than males to report subjective measures of severity. Another publication in FY 2004 focused on a 2-year follow-up study of a subset of 215 ACCESS patients. The investigators reported that about 80 percent of subjects had improved or stable pulmonary function. Patients with erythema nodosum at presentation were more likely to have improvement in the chest radiograph at 2-year follow-up. Patients with a lower annual family income were more likely to worsen with respect to dyspnea and were more likely to have new organ involvement at 2-year follow-up. The investigators concluded that in this group of sarcoidosis patients the disease tended to improve or remain stable over 2 years in the majority of patients. In a third ACCESS study, researchers interviewed participants (cases and controls) regarding occupational and nonoccupational exposures. Analysis of these data show some positive associations between sarcoidosis and specific occupations, e.g., agricultural employment, exposures to insecticides at work, environments with mold/mildew, and microbial bioaerosols. However, a history of smoking cigarettes was less frequent among cases than the controls. The study did not identify a single, predominant cause of sarcoidosis.
Blood Diseases and Resources Programs
Acquired Aplastic Anemia
Acquired aplastic anemia is an unusual hematologic disease in which the bone marrow fails to produce red cells, white cells, and platelets resulting in severe anemia, low white blood cell counts, and low platelet counts. The NHLBI Division of Intramural Research conducts clinical and laboratory research on bone marrow failure syndromes, including aplastic anemia. Intramural researchers have conducted multiple laboratory experiments directed at the pathophysiology of aplastic anemia as well as clinical programs dedicated to the treatment of the disease by immunosuppression and stem cell transplantation. Recently, the intramural program completed two clinical trials testing treatments for mild and severe aplastic anemia and a study of molecular clonotyping of the T-cell response in patients with aplastic anemia. They also described mutations in the telomere repair complex genes in patients with apparent acquired aplastic anemia.
Cooley’s anemia (also called beta-thalassemia, thalassemia major, or Mediterranean anemia) is a genetic blood disease that results in inadequate production of hemoglobin. Individuals affected with Cooley's anemia require frequent and lifelong blood transfusions to sustain life. Because the body has no natural means to eliminate iron, the iron contained in transfused red blood cells builds up over many years and eventually becomes toxic to tissues and organ systems. Many children with Cooley’s anemia have acquired other diseases such as hepatitis through years of transfusion exposure. Extramural research efforts of the NHLBI include identifying mutations in the globin gene cluster that lead to Cooley’s anemia, determining the mechanism by which naturally occurring mutations significantly increase levels of fetal hemoglobin (Hb F) in adult red blood cells, developing therapeutic applications related to the naturally occurring mutations, studying iron chelation, identifying clinically useful therapies and drugs for the disorder, and developing gene therapy strategies to reduce morbidity and mortality associated with Cooley’s anemia.
Currently, researchers are exploring new methods of transfusion therapies. For example, less toxic methods of stem cell transplantation are being developed that may be useful for patients with thalassemia. New iron chelators are also being evaluated. The Cooley’s Anemia Clinical Research Network has designed protocols that will provide clinically useful information in the areas of hepatitis and new chelator development as well as insight into the potential utility of hemoglobin F induction. The network is completing a study measuring bone mass that shows that a significant decrease in bone mass occurs in all forms of thalassemia. The decrease in bone mass becomes progressively greater with age and is affected by weight and growth hormone deficiency.
Several new therapies are being developed to treat Cooley’s anemia. Compounds that increase hemoglobin F levels have been described. The compounds include not only hydroxyurea, which is routinely used to treat sickle cell disease, but also a number of butyrate-based compounds as well as 5-azacytidine and decitabine. A new study is under way to compare the effects of deferoxamine (DFO) with deferiprone (L1) in reducing iron overload. As with other severe anemias associated with hemolysis, patients with thalassemia major suffer from pulmonary arterial hypertension (PAH) as demonstrated by increased tricuspid valve regurgitation velocities and by high pulmonary artery pressures. Patients with PAH are at higher risk of death resulting from acute pulmonary episodes including thromboembolisms. A new study is under way to test the efficacy of sildenafil in reducing PAH in thalassemia and sickle cell patients and thereby reducing morbidity and mortality.
Creutzfeldt-Jakob disease (CJD) is a slow degenerative disease of the central nervous system that is characterized by motor dysfunction, progressive dementia, and vacuolar degeneration of the brain. The disease is rare but invariably fatal and is associated with a transmissible agent. A protease-resistant protein or prion is the hallmark of all transmissible spongiform encephalopathies (TSE) including CJD. Therefore, the term prion diseases is applied to this group of neurodegenerative illnesses, which includes bovine spongiform encephalopathy (BSE) or "mad cow disease," scrapie in sheep, and chronic wasting disease in deer and elk. Prion diseases may cross the species barrier, the most notable example being the recent cases of variant CJD (vCJD) in humans caused by consumption of beef contaminated with BSE. Classical CJD occurs worldwide at a rate of one to two cases per million per year.
The lack of a rapid, sensitive, and specific test for TSE infectivity has slowed progress in the study and control of CJD and other prion diseases. Development of assay systems that could be used for blood/tissue donor screening and for detecting disease in the preclinical stage is a high priority. The assays could also be useful in testing for TSE in animals, especially in domestic animals used for human consumption. A major goal of several NHLBI programs is to develop tests that detect TSE in asymptomatic individuals that would be suitable for screening the U.S. blood supply. The NHLBI and the National Institute of Neurological Disorders and Stroke are jointly supporting an extramural contract program to develop tests to detect TSE diseases. TSE agents are at such low concentrations in the blood of laboratory animals that they cannot be detected using current methods. Investigators are developing procedures to concentrate the agents so that they can be detected with current assays. The NHLBI also supports a grant focused on developing a test to detect low levels of abnormal prion proteins based on fluorescence of the abnormal proteins.
Fanconi anemia (FA) is an autosomal-recessive bone marrow failure syndrome characterized by a decrease in blood cells and platelets, developmental defects, and cancer susceptibility. Many FA patients can be identified at birth because of congenital anomalies, although approximately 25 percent do not have birth defects. FA is a clinically heterogeneous disorder; it can currently be divided into at least eight complementation groups designated A through G. The NHLBI supports studies designed to identify and clone the remaining FA genes. An ongoing NHLBI program project has taken a multidisciplinary approach to identify causes of FA at the molecular and cellular level. The scientific areas represented in the program include molecular hematology, molecular genetics, mouse genetics, gene therapy, stem cell biology, and DNA repair. Continued efforts to develop protocols for the efficient identification and targeting of hematopoietic stem cells, to obtain information on how ex vivo manipulation of stem cells alters their biologic properties, and to improve vectors are expected to make significant contributions to understanding the pathophysiology of FA and enhancing the potential for a cure. Cord blood banking is another area of great potential benefit for hemoglobinopathy families. The NHLBI is currently supporting an investigator-initiated cooperative agreement to conduct sibling donor cord blood banking and transplantation.
Thus far, eight distinct forms of FA have been reported, suggesting that at least eight genes are involved in its manifestations. Two FA genes, FA-C and FA-A, account for an estimated 75 percent of all FA patients. More recent studies have identified a new FA complementation group (FA-L). FA-L is thought to play a critical action in gene repair. A number of studies are currently in progress to determine the causes of developmental abnormalities in FA. Ongoing studies are expected to continue to provide insight into the potential function of the abnormal proteins of Fanconi syndromes. The cellular localization of a functional protein complex that plays a role in DNA repair and prevention of mutagenesis have been exciting developments over the past few years. The interaction of the FA proteins with a breast cancer susceptibility gene (BRCA1) in a common pathway is another area of intense study. Rejection after allogeneic bone marrow transplantation for FA is another important research area since rejection remains a complication with a high risk of mortality. Recently, treatment with antilymphocyte globulin has shown promise for preventing rejection. In the study, rejection of a second allogeneic graft in a child with FA was reversed by antilymphocyte globulin and donor lymphocyte infusion.
Hemophilia is a hereditary bleeding disorder caused by a deficiency in either blood coagulation factor VIII or factor IX. The approximately 20,000 individuals in the United States with hemophilia are dependent on lifelong treatment to control periodic bleeding episodes. The NHLBI supports a broad spectrum of activities on blood coagulation and its disorders. Hemophilia research includes viral and nonviral approaches for gene therapy, mechanisms of antibody inhibitor formation, modification of factors for improved therapeutics, safety of plasma-derived products, and blood product-associated infections. In addition, basic genetic, molecular biology, and protein biochemistry studies of factors VIII and IX are supported to improve understanding of their mechanism and regulation. Two NHLBI-funded Program Project Grants support studies of gene-based therapies for hemophilia A and B and of other new therapies with a focus on treatment of patients who develop antibodies that neutralize replacement factor VIII.
Recently, NHLBI-supported investigators demonstrated the potential for using platelets as a source for the delivery and release of factor VIII protein at a site of injury. Scientists produced factor VIII-containing platelets from megakaryocytes expressing the factor VIII gene. Expression of factor VIII in platelets resulted in partial correction of the hemophilia A phenotype in mice. Investigators also are pursuing bioengineering strategies for improved secretion of factor VIII, which could enhance gene therapy approaches and increase production of recombinant factor VIII. A modified form of factor VIII was shown to be expressed 15- to 25-fold more efficiently than unmodified factor VIII. Other new research is exploring the use of activated factor VII in a gene transfer approach for treatment of hemophilia patients. Long-term expression and phenotypic correction of hemophilia B in mice was observed following adeno-associated virus (AAV) vector delivery of modified factor VIIa.
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (HHT) (or Osler-Weber-Rendu disease) is a bleeding disorder caused by weakness of the vascular support structure. Its most common manifestations are red spots on the lips and bleeding from mucosal membranes such as in the nose. In an advanced stage, arterio-venous malformations often develop in the lung, brain, gut, and liver. Two gene defects have been identified in patients with HHT. One is in a gene associated with the protein endoglin and the other is in a gene related to activin receptor-like kinase. A correlation may exist between the gene defect and organ susceptibility to the disease. The NHLBI supports a broad spectrum of research in hemostasis and thrombosis that is focused in part on understanding the biology of platelet activation, the mechanism of clotting, and the interaction of blood with the vascular surface.
The lymphatic system regulates the flow of fluid that surrounds cells. Lymphedema occurs when the lymphatic system becomes unbalanced. The two major types of lymphedema are primary (congenital) lymphedema and secondary lymphedema (caused by tissue injury, scarring, cancer, lymph node removal, or infection). The NHLBI is interested in finding the developmental, molecular, and cellular causes of lymphedema as well as designing better therapies for both primary and secondary lymphedemas. Relevant NHLBI-funded projects include: Regulation of Angiogenesis by SLP-76 Signaling, Genes for Vascular Morphogenesis: a Genetic Approach, Influences of Lymph Flow on the Lymphatic Pump, Physiological Basis of Vascular Contractility, Lymph vs. Blood Angiogenesis: Functional Differences, Prox1 in Mammalian Lymphangiogenesis, FOXC2 in Hereditary Lymphedema, Control of the Lymphatic Endothelial Differentiation Program, and Molecular Characterization of Familial Lymphedema.
Paroxysmal Nocturnal Hemoglobinuria (PHN)
Paroxysmal nocturnal hemoglobinuria (PHN) is a disease of the bone marrow in which acquired, somatic mutations in the PIG-A gene lead to expansion of a clone of cells unable to express glycosylphosphatidylinositol-anchored proteins on their surface. The disorder results in intravascular hemolysis, proclivity to venous thromboses, and bone marrow failure. The NHLBI intramural program conducts clinical and laboratory studies in bone marrow failure syndromes, including PHN. Researchers in the intramural program of the NHLBI have used microarray technology to characterize the transcriptome in hematopoietic progenitor and stem cells of the PHN clone. They have also determined that clonal preleukemic diseases can arise in PNH patients from non-PIG-A-mutated clones. Currently, intramural researchers are participating in the planning of Alexion’s clinical trial of eciluzamab, a monoclonal antibody of potential utility in blocking intravascular hemolysis.
Sickle Cell Disease
Sickle cell disease (SCD) is an inherited blood disorder that is most common among people whose ancestors come from Africa, the Middle East, the Mediterranean basin, and India. In the United States, approximately 50,000 individuals, primarily African Americans, have sickle cell disease (SS hemoglobin). One of every 650 African Americans (0.15 percent) is born with sickle cell disease, and about 8 percent are heterozygous for the sickle cell gene. Sickle cell disease occurs when an infant inherits the gene for sickle hemoglobin from both parents (Hb SS = sickle cell anemia) or the gene for sickle hemoglobin from one parent and the gene for another abnormal hemoglobin from the other parent (sickle cell disease types, e.g., Hb SC, Hb S-Beta thalassemia). In patients with the disease, the abnormal hemoglobin molecules tend to damage the red cells, causing them to stick to blood vessel walls. This leads to the acute painful episodes that are the hallmark of the disease. It also leads to chronic damage to the brain, heart, lungs, kidneys, spleen, and liver. The median age at death for patients with sickle cell disease is 42 years for men and 48 years for women. Pulmonary complications account for a large proportion of deaths among adults with sickle cell anemia. According to the Cooperative Study of Sickle Cell Disease (CSSCD), in a prospective multicenter study of 3,764 patients, over 20 percent of adults had fatal pulmonary complications of sickle cell anemia. Acute and chronic pulmonary complications of sickle cell anemia such as pulmonary hypertension, pulmonary fibrosis, and asthma are also common.
Over the last 5 years the NHLBI, the NIH Clinical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases have created a unified consortium of intramural investigators that is one of the largest sickle cell disease translational research programs in the country. The consortium has enrolled over 400 patients with sickle cell anemia and over 100 control subjects (48 African American) into six IRB-approved protocols. The largest of the protocols is addressing the prevalence, etiology, and treatment of secondary pulmonary hypertension, a leading cause of adult mortality in patients with sickle cell disease. The clinical program is complemented by a basic science program focusing on pathophysiology and experimental therapeutics. Current research in the NHLBI intramural program is determining the role of nitric oxide in the pathogenesis and treatment of sickle cell disease, characterizing the emerging syndrome of hemolytic anemia-associated secondary pulmonary hypertension, and identifying new therapeutic targets. In the last 2 years, three potential new therapeutic approaches (statin therapy, NO gas inhalation, and sildenafil/L-arginine therapy) have been identified and are being addressed in ongoing clinical trials.
The current NHLBI sickle cell disease extramural research portfolio includes research on the following topic areas: (a) development of methods for gene addition to the hematopoietic stem cell, (b) characterization of interactions between sickled cells and the vascular endothelium, (c) improved understanding of hemoglobin gene switching to allow increased production of fetal hemoglobin, (d) a phase III clinical trial (STOP II) to evaluate the use of blood transfusion to prevent strokes in children with abnormal blood velocities, (e) a phase III clinical trial (BABY HUG) of hydroxyurea (HU) to determine if HU can prevent the onset of chronic end-organ damage in very young children with SCD, (f) production of an anti-B19 parvovirus vaccine for clinical trials in healthy volunteers and pediatric SCD patients, and (g) an epidemiologic study of adult patients who participated in the Multicenter Study of Hydroxyurea (MSH) Trial.
In FY 2004, NHLBI-funded investigators published papers on pulmonary hypertension in patients with SCD, blood mononuclear cell gene expression, biological activity of nitric oxide, and the role of inhaled nebulized nitrite. One highlight of research published in the past year was a report on the high prevalence of pulmonary hypertension and risk of death in adult patients with SCD. Despite having lower pulmonary-artery pressures and higher cardiac outputs than patients with primary pulmonary hypertension, patients with SCD and pulmonary hypertension had a significantly higher mortality rate than patients with SCD who did not have pulmonary hypertension. Researchers found that a tricuspid regurgitant jet velocity of at least 2.5 meters per second, as compared with a velocity of less than 2.5 meters per second, was strongly associated with an increased risk of death even after adjusting for other possible risk factors. The findings suggest that noninvasive measurement of tricuspid regurgitant jet velocity by echocardiography can be used to identify patients at high risk for death. The results support the use of Doppler echocardiographic screening in all adults with sickle cell disease to identify those patients at high high risk who may benefit from intervention. Therapeutic trials of oxygen, warfarin, transfusion, and pulmonary vasodilator and remodeling medications are required to evaluate their potential to decrease the substantial morbidity and mortality associated with pulmonary hypertension.
Another important study published in 2004 evaluated the effects of the NHLBI-sponsored Stroke Prevention Trial in Sickle Cell Anemia (STOP). Although STOP demonstrated the efficacy of blood transfusions for primary stroke prevention in high-risk children with SCD, the effect of this trial on public health had not been studied. Investigators in California recently sought to determine whether stroke rates in California among children with SCD have declined since the STOP findings were released in 1998. Using a state-wide hospital discharge database, they identified all first admissions for stroke in children with SCD from 1991 through 2000. The investigators observed declining stroke rates in children with SCD, coincident with the publication of the STOP study. Further studies are needed to demonstrate the causality of the association and to explore in greater detail both the implementation and benefit of transfusion therapy. The public health implications of this issue are great because of the substantial costs of blood transfusion therapy and the substantial potential benefit.
Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE) is an autoimmune disorder in which the body produces antibodies that harm its own cells and tissues. Typical symptoms include fatigue, arthritis, fever, skin rashes, and kidney problems. SLE affects more women than men. The risk of coronary heart disease in women with SLE is up to 50 times higher than in the general population. SLE patients have a higher incidence of blood clot formation (thrombosis) and spontaneous loss of pregnancy. Although its cause remains unknown and no cure is currently available, SLE symptoms can be controlled with appropriate treatment so that most patients can lead an active life. The NHLBI supports two major areas of research relevant to SLE. First, the NHLBI funds research on components of the blood that regulate bleeding and blood clotting (hemostasis and thrombosis) to understand the biology of platelet molecule function, mechanisms of blood clotting, and the interaction of blood components with blood vessel (vascular) surfaces. Second, the NHLBI funds research on cardiovascular complications and risk factors that may help explain the elevated incidence of premature cardiovascular disease in women with SLE. Such factors include the presence of antibodies to phospholipid-binding proteins, which are present in 50 percent of SLE patients versus only 1–5 percent of healthy individuals. In addition, research is being conducted to study the role of inflammation and oxidative stress in SLE. One group of NHLBI-funded investigators recently completed studies to identify atherosclerotic risk factors in a young population of SLE patients. Another group of researchers conducted a cross-sectional study to measure atherosclerosis in women with SLE who did not have cardiovascular disease. The study found that risk factors associated with vascular stiffness seem to include some SLE-specific variables that are likely to be related to immune regulation.
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease characterized by low blood platelet levels and widespread platelet thrombi in arterioles and capillaries. The disease has a sudden onset and individuals with TTP often exhibit hemolysis, high fever, and neurological abnormalities. Management of patients with TTP is difficult due to the lack of specific diagnostic criteria and rapid progression of disease. The standard therapy for TTP is plasma exchange. Relapse after the acute phase is common. The clinical course differs significantly for patients with idiopathic TTP compared to patients with TTP provoked by predisposing conditions. A congenital or acquired deficiency of a plasma metalloprotease, ADAMTS 13, that cleaves large polymers of von Willebrand factor (vWF) has been linked to the disease. Despite advances in basic research on TTP, rapid and reliable assays for ADAMTS 13 for clinical use are lacking, treatment options are limited, and mortality remains high. The NHLBI supports a broad spectrum of research in hemostasis and thrombosis that includes research on platelet biology, blood coagulation, and the interaction of blood with the vascular surface. Recently, grants specifically targeted to TTP have been awarded. In addition, efforts are under way to develop rapid and specific assays for ADAMTS 13 and to produce recombinant ADAMTS 13 on a large scale.
NHLBI-supported grantees have made fundamental contributions toward the discovery of ADAMTS 13 and the understanding of TTP. The observation that an antibody to ADAMTS 13 may cause TTP was a major breakthrough in the field. Researchers now know that a deficiency of the protease causes both congenital and acquired TTP (antibody induced). A recent study demonstrated variable performances of available assays that measure ADAMTS 13 but provided an optimistic view about the reliability of currently available methods for measuring the protease level. Recently, a new enzyme immunoassay (EIA) for measuring the activity of ADAMTS 13 in plasma samples of patients has been described. The EIA could distinguish patients from normal individuals or carriers of one copy of mutant ADAMTS 13 allele. The EIA method is simple and could be adapted for general use in clinics. Overall, new assays correlate well with diagnostic categories, the response to plasma exchange, and the likelihood of relapse. A recent study showed that inflammatory cytokines may regulate the processing of vWF by ADAMTS 13. The finding may lead to new therapeutic interventions for patients with TTP and other inflammation-associated thrombotic disorders.
Rare Diseases Research Initiatives
- Animal Models of Antigen-Specific Tolerance for Heart and Lung Transplantation
- Beryllium-induced Diseases
- Biology of Iron Overload and New Approaches to Therapy
- Blood and Marrow Transplant Clinical Research Network
- Cell-based Therapies for Heart, Lung, Blood, and Sleep Disorders and Diseases
- Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension
- Chemical and Genetic Screens for New Inducers of Fetal Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooley’s Anemia
- Chemical Genomics and Molecular Libraries for Sickle Cell Disease
- Chronic Fatigue Syndrome: Pathophysiology and Treatment
- Comprehensive Sickle Cell Centers
- Coordination of Vascularization and Lung Development
- Cord Blood Transplantation Study
- Developmental Processes in Differential Expression of Globin Genes
- Development of an Assay for Crutzfeldt-Jakob Disease
- Diamond-Blackfan Anemia and Other Congenital Bone Marrow Failure Syndromes: Underlying Molecular Mechanisms
- Functional Heterogeneity of the Peripheral, Pulmonary, and Lymphatic Vessels
- Genetic Aspects of Tuberculosis in the Lung
- Genetic Modifiers of Single Gene Defect Diseases
- Granulomatous Lung Inflammation in Sarcoidosis
- Hemophilia and Hereditary Bleeding Disorders: Improved Therapy
- Heritable Disorders of Connective Tissue
- Hutchinson-Gilford Progeria Syndrome: Exploratory/Developmental (R21) Grants
- Idiopathic Pulmonary Fibrosis Clinical Research Network
- International Cooperative Biodiversity Groups (ICBG)
- Marfan Syndrome: National Registry
- Mechanisms of Fetal Hemoglobin Gene Silencing for Treatment of Sickle Cell Disease and Cooley's Anemia
- Mesenchymal Stem Cell Biology
- Molecular Mechanisms of Mucous Cell Metaplasia and Excess Mucous Secretion in Human Airway Diseases
- Multicenter Study of Hydroxyurea in Sickle Cell Disease: Patient Follow-Up Extension I
- Myelodysplastic Syndromes (MDS): Pathogenesis and Disease Progression
- Myeloproliferative Disorders (MPD): Pathogenesis and Disease Progression
- NHLBI Clinical Proteomics Programs
- NHLBI Lung Tissue Resource
- Novel Approaches to Enhance Animal Stem Cell Research
- Oxygen Sensing During Intermittent Hypoxia
- Pathogenesis and Treatment of Lymphedema and Lymphatic Diseases
- Pathogenesis of SARS Lung Disease: In vitro Studies and Animal Models
- Pediatric Heart Disease Clinical Research Network
- Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)
- Pediatric Mechanical Circulatory Support
- Plasticity of Human Stem Cells in the Nervous System
- Programs for Genomic Applications (PGAs) for Heart, Lung, and Blood Research
- Programs of Excellence in Gene Therapy (PEGT) for Heart, Lung, and Blood Diseases
- Pulmonary Complications of Sickle Cell Disease
- Pulmonary Fibrosis: Molecular Targets and Interventions
- Rare Diseases: Exploratory and Developmental Research Grants
- Sickle Cell Disease Clinical Research Network
- Sildenafil for Sickle Cell-Associated Pulmonary Hypertension: Phase II/III Clinical Trial
- Somatic Cell Therapy Processing Facilities
- Specialized Centers of Clinically Oriented Research (SCCOR) in Pediatric Cardiovascular Disease
- Specialized Centers of Clinically Oriented Research (SCCOR) in Pulmonary Vascular Disease
- Specialized Centers of Research (SCOR) in Hematopoietic Stem Cell Biology
- Specialized Centers of Research (SCOR) in (a) Neurobiology of Sleep and Sleep Apnea and (b) Airway Biology and Pathogenesis of Cystic Fibrosis
- Specialized Centers of Research (SCOR) in Pathobiology of Fibrous Lung Disease
- Stem Cell Plasticity in Hematopoietic and Non-hematopoietic Tissue
- Thalassemia (Cooley's Anemia) Clinical Research Network
- Transactivation of Fetal Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooley’s Anemia
- Transfusion Medicine/Hemostasis Clinical Research Network
- Treatment of HIV and Associated Complications in Hemophiliacs
- Tuberculosis Curriculum Coordinating Center
- Vascular and Hematopoietic Development and Disease
Initiatives Started in 2004
Diamond-Blackfan Anemia and Other Congenital Bone Marrow Failure Syndromes: Underlying Molecular Mechanisms
A new NHLBI-initiated Request for Applications (RFA) promotes research on the genetics and biochemical mechanisms of Diamond-Blackfan anemia and other rare inherited bone marrow failure syndromes. An understanding of the molecular pathways disrupted in the syndromes will facilitate development of targeted therapies and stimulate research on the molecular mechanisms underlying defective hematopoiesis, congenital anomalies, and cancer development in marrow failure diseases. Other diseases that are related to this initiative include dyskeratosis congenita, Pearson syndrome, severe congenital neutropenia (Kostmann syndrome), Shwachman-Diamond syndrome, and congenital amegakaryocytic thrombocytopenia.
Granulomatous Lung Inflammation in Sarcoidosis
A new NHLBI-initiated RFA supports research on the immunopathogenic mechanisms that lead to a nontuberculous granulomatous inflammation in the lungs of individuals with sarcoidosis. Research focuses on investigating the etiology of sarcoidosis, determining its susceptibility factors, and identifying the components of the innate and/or adaptive immune pathways that affect lung lymph nodes and tissue.
NHLBI Lung Tissue Resource
A new NHLBI-sponsored Broad Agency Announcement (BAA) establishes and supports a program for the standardized processing, storage, and distribution of lung tissues and associated clinical data. The resources will enable investigators to perform studies correlating molecular histopathology of the lung with pulmonary function and clinical status. Tissues will be procured and processed from 500 smoking and nonsmoking subjects with essentially normal lungs and from 2,000 subjects with pulmonary disease. The majority of those with disease will have COPD and will be extensively characterized with respect to airflow limitation and CT measures of emphysema. Lung specimens will also be obtained, when possible, from individuals with pulmonary fibrosis, sarcoidosis, asthma, primary pulmonary hypertension, and other serious chronic diseases that affect the lungs.
Pathogenesis and Treatment of Lymphedema and Lymphatic Diseases
A renewal of an NHLBI-initiated, trans-NIH Program Announcement (PA) investigates the pathogenesis of, and new treatments for, primary and secondary lymphedema. Lymphedema may be a congenital condition or may arise as a result of surgery, radiation, or the presence of a tumor in the area of the lymph nodes. Research will focus on the biology of the lymphatic system, the pathophysiologic mechanisms that cause lymphedema and lymphatic diseases, methods for quantitating and imaging lymph flow, therapeutic interventions, and mechanisms of action of complementary and alternative therapies. New knowledge in lymphatic disease research should improve early diagnosis of affected individuals, choice and timing of treatment, and genetic counseling.
Pediatric Mechanical Circulatory Support
A new BAA, initiated by the NHLBI, supports development of mechanical assist devices, including extracorporeal membrane oxygenation (ECMO) systems, left ventricular assist devices (LVADs), and other bioengineered systems for children with congenital and acquired cardiovascular disease. The program provides basic physiological and bioengineering data necessary for the design of effective pediatric assist and replacement devices while also supporting phase I studies to explore innovative strategies to meet the clinical needs of the pediatric patient population.
Programs for Genomic Applications for Heart, Lung, and Blood Research
A renewal of an NHLBI-initiated RFA links the genomic resources and tools of the Human Genome Project (HGP) to studies of major biological processes and systems involved in cardiovascular, pulmonary, hematologic, and sleep function and dysfunction through the establishment of 11 Programs for Genomic Applications (PGAs) for Heart, Lung, and Blood Research. The PGAs identify subsets of genes that are particularly relevant to the biology, diagnosis, management, treatment, and prevention of heart, lung, blood, and sleep-related disorders and prioritize the information for further focused study. The generation and interpretation of data from the PGAs enables a broad range of investigators to exploit the opportunities provided by the HGP and related technologies. In addition, the PGAs support training and education programs for NHLBI-supported investigators in the use of genomic information and technologies. The 11 PGAs will continue to collaborate to develop common protocols, standard procedures, and nonredundant education and training efforts.
Rare Diseases: Exploratory and Developmental Research Grant
A new PA, initiated by the NHLBI and co-sponsored by the Office of Rare Diseases, encourages research on understanding, treating, and preventing rare heart, lung, and blood diseases as well as sleep disorders. Rare diseases are often referred to as "orphan" diseases since there is a general lack of interest among industries to invest resources in diseases that in aggregate affect too few people to guarantee a reasonable return on investment. The availability of R21 exploratory and developmental awards is expected to allow investigators with new ideas to obtain research support without the need for large amounts of preliminary data, a requirement that can serve as a barrier to obtaining other types of awards.
Initiatives Planned for the Future
Chronic Fatigue Syndrome: Pathophysiology and Treatment
A renewal of a trans-NIH PA, sponsored in part by the NHLBI, will investigate the pathophysiology and treatment of chronic fatigue syndrome (CFS) in diverse groups and across the life span to improve the diagnosis, treatment, and quality of life of all persons with CFS. Research on new hypotheses, heterogeneous population groups, research gaps, and common mediators influencing the actions among and between various bodily systems will be encouraged. Topics of special interest to the NHLBI include: (1) the role of neuro-cardiovascular regulation in the loss of normal control of blood pressure, heart rate, and contractility in CFS patients and (2) factors and mechanisms involved in altered sleep state, circadian regulation, and other causes of impaired or ineffective sleep in CFS patients.
Hemophilia and Hereditary Bleeding Disorders: Improved Therapy
A new RFA, to be initiated by the NHLBI in FY 2005, will improve understanding of immune response and safety issues related to gene transfer or cell-based therapies for bleeding disorders. The objective of the research is to develop improved treatments and possibly cures for hemophilia, von Willebrand disease, and other hereditary bleeding disorders. The initiative is co-funded by the National Hemophilia Foundation, an organization promoting education, research, and advocacy on behalf of people with bleeding disorders.
Idiopathic Lung Fibrosis Clinical Research Network
In FY 2005, a new NHLBI-initiated RFA will establish a network of clinical centers to conduct multiple treatment trials on patients with established idiopathic pulmonary fibrosis (IPF), a disease of inflammation that results in scarring of the lungs and eventually interference with oxygen transport. Researchers believe that IPF may result from either an autoimmune disorder or from infection, most likely by a virus. The network will consist of approximately 10 clinical centers and a data coordinating center. Each of the clinical centers is expected to enroll 40 to 50 patients per year for a 2-year interval of treatment and 2 years of follow-up. For patients who require an open lung biopsy for diagnosis, living lung tissue and blood will be stored for future studies on cellular genomic and immunopathogenic changes.
Marfan Syndrome: National Registry of Patients
A new RFA will be initiated by the NHLBI and co-sponsored by the NIAMS in FY 2005 to establish a registry to collect and analyze clinical data and samples (e.g., blood and tissue) from patients with Marfan syndrome and to improve understanding of cardiovascular complications and therapies for the disorder. Ultimately, the registry will provide an essential resource to improve clinical care for patients.
Muscular Dystrophy: Pathogenesis and Therapies
In FY 2005 a new PA, sponsored in part by the NHLBI, will investigate the pathogenesis of muscular dystrophies (MD) and develop therapies for them. Premature death due to MD is often caused by cardiac or respiratory failure. Though recent research has increased knowledge about genetic defects associated with many forms of MD, a corresponding improvement in the treatment of MD has not been achieved. Important research priorities include studies of gene and stem cell therapies, pharmacological approaches to treatment, and clarification of the role of inflammatory mechanisms.
Myeloproliferative Disorders: Pathogenesis and Disease Progression
A new RFA, to be initiated by the NHLBI in FY 2005 and co-sponsored by the NCI, will support research on the genetic, biochemical, and molecular pathways that operate in the emergence and progression of myeloproliferative disorders (MPD), a group of conditions characterized by excessive proliferation and production of one or more of the bone marrow (myeloid) cells. Research will focus on analyzing genes that are expressed in MPD and identifying gene products that are associated with or responsible for disease development and progression to a malignant and fatal outcome. Such discoveries will be critical to the development of new therapies for MPD patients who are not suitable candidates for hematopoietic stem cell transplantation, the only curative therapy currently available.
NHLBI Clinical Proteomics Programs
In FY 2005, the NHLBI will initiate a new RFA to validate on a systematic, comprehensive, large-scale basis existing and new candidate protein markers that are appropriate for routine use in the diagnosis and management of heart, lung, blood, or sleep diseases and disorders. The initiative establishes an infrastructure for research teams to validate protein panels that may be used to predict disease susceptibility or to assist in differential diagnosis, disease staging, selection of individualized therapies, and monitoring of treatment responses. The validation process will use disease-associated biological samples and clinical data from ongoing and completed NHLBI clinical trials and epidemiologic studies. In addition, the programs will provide education and skills development to ensure that scientists have the competencies and expertise needed to address the multifaceted challenges of clinical proteomics.
Novel Approaches to Enhance Animal Stem Cell Research
In FY 2005, the NHLBI will collaborate with several Institutes to fund the renewal of a PA to support the identification, isolation, and characterization of totipotent and multipotent stem cells from biomedical animal research models. The research will generate reagents and develop techniques to characterize and separate stem cells from other cell types. The PA stresses innovative approaches to the problems of making multipotent stem cells available from a variety of non-human sources, creating reagents that will identify multipotent stem cells across species and allow for their separation from differentiated cell types.
Pathogenesis of SARS Lung Disease: In Vitro Studies and Animal Models
A new PA will be initiated by the NHLBI in FY 2005 to advance understanding of the pathogenesis of severe acute respiratory syndrome (SARS) in the lung using in vitro techniques, existing animal models of related coronavirus infections, non-human primate models of SARS, and new rodent models. Research topics of interest include in vitro research on the role of collectins and other extracellular host factors; studies of endothelial and epithelial permeability; and investigations of the effects of SARS on fluid movements, growth, and differentiation of human lung cells (e.g., alveolar epithelial cells, fibroblasts). The primary focus is on human SARS coronaviruses, but research using engineered and related animal coronaviruses and animal cells pertinent to the pathogenesis of SARS may also be conducted.
Programs of Excellence in Gene Therapy for Heart, Lung, and Blood Diseases
A renewal in FY 2005 of an NHLBI-initiated RFA will promote the rapid translation of basic, preclinical studies of gene therapy for cardiovascular, pulmonary, and hematologic diseases into pilot studies in humans. During their second 5-year operating period, the NHLBI Programs of Excellence in Gene Therapy (PEGT) will: (1) conduct preclinical projects to facilitate the translation of gene therapy into clinical studies; (2) conduct clinical phase I/II studies to test the safety and efficacy of gene therapy procedures; (3) operate six national cores to provide no-cost resources and services to NHLBI-supported investigators conducting gene therapy research; and (4) train M.D., M.D./Ph.D., and Ph.D. scientists in conducting gene therapy clinical trials.
Pulmonary Complications of Sickle Cell Disease
In FY 2005, a new RFA will be initiated by the NHLBI to conduct basic and clinical research on pulmonary complications of sickle cell disease (SCD). Acute sickle cell chest syndrome, the second most common acute clinical complication of SCD, is characterized by infiltrates in the lungs and sometimes by fever, pneumonia, and thromboembolism of peripheral blood clots and/or fat emboli. The less common chronic form of sickle cell lung disease is characterized by pulmonary perfusion and diffusion defects, pulmonary hypertension, changes in the vessel walls such as intramural and perivascular connective tissue deposition, hyperplasia/hypertrophy of smooth muscle cells, and in some cases by intramural thrombosis. Further elucidation of the acute and chronic lung syndromes is required in order to develop more adequate therapies.
Thalassemia Clinical Research Network
In FY 2005, the NHLBI will renew an RFA to continue operation of a cooperative network of five clinical centers and a data coordinating center conducting clinical trials to evaluate existing and future therapies for the treatment of thalassemia major (Cooley's anemia). The network enhances progress in moving effective therapies, e.g., fetal hemoglobin enhancing agents, gene therapy, or iron chelation, from the laboratory to the bedside through rapid and systematic collaborative testing in phase II and phase III clinical trials. A registry of thalassemia patients has also been developed and will be used to identify patients available for future trials.
Sickle Cell Disease Clinical Research Network
A new RFA, which will be initiated by the NHLBI in FY 2006, will establish a clinical research network to conduct multiple phase III randomized, controlled clinical trials to test the efficacy of new therapies to treat and prevent complications of sickle cell disease and, when appropriate, thalassemia. The interventions will be based on results from basic studies and phase I and phase II clinical trials conducted in programs such as the NHLBI Comprehensive Sickle Cell Centers Program. The network will comprise a data coordinating center and up to 15 clinical centers that will enroll 50 or more patients per center per year to participate in multiple trials using common protocols. In addition, the network is designed to create datasets that can be used to characterize patients and their clinical course, apply genomic and proteomic techniques for improved diagnostic and therapeutic approaches, expand clinical application of multimodal therapies, and examine patient-centered outcomes.
Specialized Centers of Clinically Oriented Research in Pulmonary Vascular Disease
In FY 2005, the NHLBI will initiate a new RFA to conduct multidisciplinary research on clinical questions related to the diagnosis, prevention, and treatment of pulmonary vascular disease. The program will address primary (idiopathic) and secondary pulmonary arterial hypertension, acute and chronic pulmonary thromboembolism, right ventricular dysfunction, and pulmonary vascular disorders of infants and children. Three to four centers will each carry out a minimum of three research projects directly related to a unifying theme. At least half of the projects in each center will be clinically oriented to assure that basic science findings are rapidly applied to clinical problems. Applicants may propose inclusion of a Clinical Research Skills Development Core to enhance the research skills of new clinical investigators.
Rare Disease-related Program Activities
Alpha-1 Antitrypsin Deficiency
The NHLBI sponsored an education strategy development workshop on chronic obstructive pulmonary disease on September 22–23, 2004, in Arlington, Virginia. The purpose of the meeting was to develop priorities for improving awareness and knowledge of alpha-1 antitrypsin (AAT) deficiency and chronic obstructive pulmonary disease (COPD).
The NHLBI held a workshop titled “Critical Issues in COPD Research” on September 28–29, 2004, in Bethesda, Maryland. Recommendations were made regarding priorities for future scientific research on AAT deficiency-related lung disease and COPD.
Arrhythmogenic Right Ventricular Dysplasia
NHLBI-funded investigators have produced an informational brochure titled “Physicians Guide to Diagnosis of ARVD” and distributed it to the membership of the Heart Rhythm Society.
NHLBI-funded investigators recently produced a third volume of the newsletter “Lo Que Pasa, Newsletter of the Multidisciplinary Study of Right Ventricular Dysplasia.”
The NHLBI sponsored the annual meeting of the Collaborative Program for Research in BPD, which was held on September 23–24, 2004, in Bethesda, Maryland.
Congenital Central Hypoventilation Syndrome
The NHLBI co-sponsored the Eighth International Conference on Sleep and Breathing on October 13–16, 2004, in Newport, Rhode Island. Many of the discussions were directly related to the control of breathing in a variety of sleep disorders.
Congenital Heart Disease
Five Pediatric Circulatory Support contracts were awarded in 2004. The five contracts provide for development of a wide range of pediatric ventricular assist devices (VADs): a fully implantable, miniature centrifugal pump; infant- and child-sized pulsatile flow VADs; an innovative, small, extracorporeal membrane oxygenation device; a miniature axial flow VAD for the entire range of pediatric patient sizes; and infant- and child-sized axial flow pumps based on a more standard VAD design.
The Weinstein Cardiovascular Development Conference is an annual meeting partially supported by NHLBI. The 2004 meeting was held on May 13–16, 2004, in Noordwijkerhout, The Netherlands. The meeting included reports by NHLBI-supported investigators on congenital heart disease.
On April 17, 2004, the NHLBI convened a meeting titled “Future Directions in the Hemoglobinopathies” to bring together investigators active in research on hemoglobin disorders. Attendees discussed the feasibility of a future clinical research network for both SCD and beta-thalassemia. Currently, the NHLBI supports two separate networks—one for SCD and one for thalassemia. However, several research topics now under study have therapeutic potential for both diseases. While both communities have some specific concerns, the overall concept was endorsed by the attendees.
The NHLBI held a meeting for investigators with projects funded through RFAs related to hemoglobin disorders on September 22–24, 2004.
On October 4, 2004, a number of investigators supported by the NHLBI and the NIDDK met to discuss progress in their research to improve the utility of MRI as a method for quantitative determinations of tissue iron, especially in liver, heart, and brain.
The Weinstein Cardiovascular Development Conference is an annual meeting partially supported by the NHLBI. The 2004 meeting was held on May 13–16, 2004, in Noordwijkerhout, The Netherlands. The meeting included reports by NHLBI-supported investigators on congenital heart disease.
The fifteenth annual FA Research Fund Scientific Symposium was held on October 16–19, 2003, in Houston, Texas, with 46 researchers presenting to over 150 participants from 11 countries. The meeting was sponsored by the Fanconi Anemia Research Foundation.
A recombinant porcine Factor VIII is being developed by Octagen Corporation, with SBIR support, as a treatment option for hemophilia A patients who develop antibody inhibitors that neutralize the activity of currently available types of replacement Factor VIII.
Long QT Syndrome
Several NHLBI-funded scientists participated in developing new guidelines to identify and prevent acquired LQTS from occurring as an unwanted side effect of drug therapy.
The NHLBI, the Office of Rare Diseases, and the LAM Foundation co-sponsored the LAM Research Conference in Cincinnati, Ohio, March 26–28, 2004.
The first ever Gordon Conference on lymphatic biology titled “Molecular Mechanisms in Lymphatic Function and Diseases,” sponsored in part by the NHLBI, was held March 7–12, 2004, in Ventura, California.
Primary Pulmonary Hypertension
The Pulmonary Hypertension Association (PHA) is collaborating with the NHLBI to support new Career Development Award (K08-K23) investigators who are conducting research projects on PPH.
The NHLBI provided support for the 2004 Grover Conference on “Genetic and Environmental Determinants of Pulmonary Endothelial Cell Function,” which was held on September 9–12, 2004, in Sedalia, Colorado.
In collaboration with the NIH Office of Rare Diseases and the Centers for Disease Control and Prevention, the NHLBI provided funding for the “PHA International Pulmonary Hypertension Conference—Scientific Session” held on June 24–27 in Miami, Florida.
The NHLBI is revising the Sarcoidosis Fact Sheet.
A representative from the NHLBI is chairperson of the recently established trans-NIH Sarcoidosis Working Group. The first meeting of the working group was held on November 1, 2004. The group is reviewing current NIH-funded research pertinent to sarcoidosis and discussing the possibility of future joint activities and initiatives.
Sickle Cell Disease
NHLBI investigators are participating in research related to a CRADA agreement between the NIH Clinical Center and INO Therapeutics. The CRADA supports a large screening trial to identify sickle cell patients with pulmonary hypertension and to treat them with inhaled NO gas. The results of the screening trial, which were published in the New England Journal of Medicine, revealed that 30 percent of sickle cell patients develop pulmonary hypertension, which is the leading cause of death in sickle cell patients.
The Comprehensive Sickle Cell Centers Steering Committee met for the fourth time on December 4, 2003, to present, discuss, and rank proposals for collaborative multicenter clinical research protocols. The Steering Committee selected 10 protocols for further development: oral arginine supplementation in children and adults; neurocognitive function in adults; a comprehensive patient registry, including epidemiology of headaches; priapism—prevalence and prevention; hydroxyurea plus magnesium for hemoglobin sickle cell disease; decitabine for fetal hemoglobin induction; pain treatment with methadone; interventional trial for headaches; interventional trial for priapism; and dexamethasone for acute chest syndrome.
On April 17, 2004, the NHLBI convened a meeting titled “Future Directions in the Hemoglobinopathies” to bring together investigators active in research on hemoglobin disorders. Attendees discussed the feasibility of a future clinical research network for both SCD and beta-thalassemia. Currently, the NHLBI supports two separate networks—one for SCD and one for thalassemia. However, several research topics now under study have therapeutic potential for both diseases. While both communities have some specific concerns, the overall concept was endorsed by the attendees.
The NHLBI convened the “Sickle Cell Consultative Network Meeting” on September 21, 2004. Adult hematologists who care for patients with sickle cell disease met to discuss improving care by providing consultation services for patients who live in parts of the United States that are not served by a Comprehensive Sickle Cell Disease Center.
On September 22–24, 2004, 25 investigators with projects funded through any one of several NHLBI RFAs related to hemoglobin disorders met to discuss research progress.
The BABY HUG Steering Committee met on September 23, 2004, to discuss progress in the ongoing pilot phase of this clinical trial. The objective of the BABY HUG trial is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in young patients with sickle cell anemia. The clinical trial will involve the cooperation of pediatric clinical centers with a medical coordinating center that will supervise drug distribution, central laboratory functions, and data collection.
The MSH Patients’ Follow-up Steering Committee Meeting met on September 24, 2004, to discuss follow-up of the MSH cohort for the next 5 years. A paper summarizing survival for the last 9 years has been published. Data from the cohort suggest that survival is improved if fetal hemoglobin levels are elevated by continuing hydroxyurea therapy.
On September 22, 2004, the STOP II Trial Steering Committee met to discuss the STOP II Trial protocol and subject recruitment. The objective of STOP II is to determine whether it is safe to stop transfusing children after 30 months for stroke prevention. The trial is now in its fourth year of funding and will be terminated early due to the accumulation of significant evidence against stopping transfusion at 30 months.
Problem Areas Related to Rare Diseases
Advanced Sleep Phase Syndrome
Because advanced sleep phase syndrome (ASPS) is a rare genetic disorder, it is difficult to recruit patients for clinical studies.
Alpha-1 Antitrypsin Deficiency
Research needs include better animal models of the disease, identification of biomarkers, identification of modifier genes, development of chemical chaperones that could specifically enhance the secretion of mutant alpha-1 antitrypsin protein, improvements in approaches to gene therapy, and new treatments to slow the progression of emphysema.
Acquired Aplastic Anemia
More research is needed to increase the response to immunosuppressive treatment, prevent relapse by improving immunosuppressive regimens, prevent the evolution of late clonal disease, describe fully the clonotypes among dominant T cells, and characterize the role of telomere repair complex genes in maintenance of normal hematopoiesis.
Arrhythmogenic Right Ventricular Dysplasia
The Multidisciplinary Study of Right Ventricular Dysplasia has had many challenges in recruiting patients/family members, primarily due to IRB delays at potential new centers and difficulty with screening families of interest due to new HIPPA requirements. Steps to streamline enrollment of family members have been put in place.
The incidence of bronchopulmonary dysplasia (BPD) has increased in recent years due to the increased survival of smaller and smaller premature infants. As a result, BPD now affects at least 10,000 very low-birth-weight (VLBW) infants each year and is associated with neonatal intensive care costs of approximately $30,000–$60,000 per infant. BPD is a multifactorial disease of developmental origin that also involves aspects of inflammation and infection. Therefore, basic research on its etiology is needed to inform meaningful clinical intervention and thereby reduce mortality, morbidity, and the associated high costs of clinical care.
Translating basic knowledge of the disease into effective therapies remains a challenge.
Congenital Central Hypoventilation Syndrome
Locating and recruiting patients remains a problem for congenital central hypoventilation syndrome (CCHS) researchers.
Congenital Diaphragmatic Hernia
More basic research is needed on the etiology of congenital diaphragmatic hernia rare disease to reduce mortality and the cost of treating survivors. The average cost of postnatal care exceeds $100,000 with even greater costs incurred for subsequent life care. Because congenital diaphragmatic hernia can now be diagnosed before birth, accurate counseling regarding the expected outcome is crucial.
Congenital Heart Disease
With the improvements in surgery made during the past 30 years, many children with congenital heart disease can now grow into adulthood. However, little systematic research has addressed the management of adults with congenital heart disease, and even fewer studies have focused on the interaction between congenital heart disease and adult cardiovascular diseases. A related concern is that many children need multiple open-heart operations to replace valves that they outgrow. Researchers using bioengineering techniques hope that in the future they will be able to develop valves that would grow with a child. In addition, better understanding of heart development is needed. It is especially important to increase understanding of: (1) the development of coronary arteries, (2) the process by which the heart develops from a symmetric tube to a complex folded structure with a distinct left and right side, and (3) the regulation of heart muscle cell division. The latter especially could be useful in adult cardiology to heal and regenerate damaged myocardium after a heart attack.
Growth and development in patients with thalassemia remains a problem. Cardiac morbidity and mortality in Cooley’s anemia (CA) patients is still a major concern. A number of co-morbidities are associated with the chronic transfusions required by people with CA, including infectious diseases (e.g., HIV and hepatitis C) and iron overload. The nature of iron toxicities and their tissue specificities require further study and new approaches to chelation therapy are needed. The morbidity and mortality associated with transplantation of hematopoietic stem cells remain unacceptably high. The potential for gene therapy remains untapped and untested in clinical studies.
During the past year, the British Government reported the first two cases of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) in transfusion recipients, the first two reports suggesting that the disease might be transmitted to people through blood transfusion. The findings support previous studies of TSE agents in laboratory animals that showed the agents to be present in blood, but in such low concentrations that current tests are not sensitive enough to detect their presence. The potential for blood transmission of vCJD points to the continued need for vigilance by governments, blood and plasma collectors, and manufacturers and underscores the need for a sensitive screening assay to detect vCJD.
Defects in any one of no less than eight different genes can cause Fanconi anemia (FA). The process of identifying the mutation responsible for a particular case of FA is complicated and cumbersome because each of the eight potential genes must be examined for mutations.
Current hemophilia replacement factor therapy requires intravenous infusions that are difficult for small children and may not provide optimal clinical outcomes. New therapeutic approaches are needed to provide a continual supply of the missing factor. Approximately 20 percent of severe hemophilia patients develop antibody inhibitors that specifically neutralize the activity of the replacement factor (e.g., factor VIII) and complicate treatment. The adult hemophilia population has been severely affected by blood-borne infectious agents in plasma-derived replacement products. Over 80 percent have been infected with hepatitis virus and approximately 20 percent are infected with HIV.
Hereditary Hemorrhagic Telangiectasia
Diagnosis of patients with vascular malformations, particularly at an early age, is difficult because multiple organs are affected. Establishment of a genetic linkage may allow earlier diagnosis and improved treatment.
Homozygous Familial Hypercholesterolemia
Very few people have homozygous familial hypercholesterolemia, making it difficult to study.
Idiopathic Pulmonary Fibrosis
Because idiopathic pulmonary fibrosis (IPF) is a rare disease, it is difficult to recruit enough patients for study. All clinical trials require a multicenter effort. To address this problem the NHLBI has established a clinical research network. To facilitate recruitment of patients, information regarding the NHLBI’s intramural trials has been placed on the NHLBI patient recruitment Web site. In addition to difficulties with recruitment, the natural course of IPF is poorly understood and no animal models exactly replicate the human disease. Only one potentially effective treatment, lung transplantation, exists.
Since very few people have Klippel-Trenaunay-Weber syndrome (KTWS), it is difficult to recruit patients for studies.
Long QT Syndrome
The lack of sufficient numbers of patients with distinct, well-defined, Long QT (LQT) mutations limits researchers’ ability to perform clinical studies of interventions. In addition, investigators are working to increase the visibility of the LQTS registry in the African-American medical community. Currently, researchers do not know whether LQTS is less common among African Americans or if they are referred to the registry with less frequency compared to the Caucasian population.
Lymphangioleiomyomatosis (LAM) tissue is scarce and cell lines are difficult to establish and maintain. In addition, more work is needed to establish relevant animal models of LAM.
Biotech and pharmaceutical companies are reluctant to invest in research on lymphedema due to a general lack of interest among industries in diseases that do not guarantee a reasonable return on investment.
Because narcolepsy is a rare disorder, it is difficult to locate and recruit patients for clinical studies.
Paroxysmal Nocturnal Hemoglobinuria
Researchers are still working on elements of the eciluzumab clinical trial protocol. More work is needed to determine the selective advantage of paroxysmal nocturnal hemoglobinuria (PHN) cells in the immune environment.
Persistent Pulmonary Hypertension of the Newborn
Even with complex and high-risk interventions such as extracorporeal membrane oxygenation, persistent pulmonary hypertension of the newborn (PPHN) currently results in substantial mortality and morbidity.
Primary Pulmonary Hypertension
Additional clinical trials are needed to determine the benefits and risks of the various therapies that have recently become available for treating primary pulmonary hypertension (PPH) and the role of combination therapy approaches to treating severe pulmonary hypertension. Because PPH is a rare disease, collaborative efforts are required in order to conduct meaningful clinical trials. Another issue is lack of access to the site of the disease, the lung blood vessels, which has severely limited the ability to study PAH at the cellular and molecular level in humans. Noninvasive methods and biomarkers to monitor pulmonary artery pressure and the course of PPH are needed.
Human tissue and animal models are needed to advance basic research on sarcoidosis. In spite of efforts by many researchers over the last half century, no etiologic agent has been identified. Better diagnostic markers and better treatments are needed. Recruiting suitable patients for clinical trials remains a problem area in sarcoidosis research.
Sickle Cell Disease
In spite of advances that have been made, several significant therapeutic and psychosocial needs for sickle cell patients remain unmet. Although bone marrow transplantation is available for approximately 20 percent of children with a matched sibling donor, the immediate prospect for a universal cure is still illusive. An understanding of the genetic factors responsible for the phenotypic differences in sickle cell disease patients’ responsiveness to infections and the wide variation in overall clinical severity is needed.
An optimized strategy of pain management for sickle crises is lacking. Prevention and management of undesirable sequealae of chronic transfusions including iron overload is needed. Exploration of psychosocial issues including transition programs from pediatric to adult care, attainment of education goals, and job retention are urgently needed.
Supravalvular Aortic Stenosis
Very few people have supravalvular aortic stenosis (SVAS), making it difficult to study.
Systemic Lupus Erythematosus
The fear of miscarriage is a great concern for pregnant women with systemic lupus erythematosus (SLE). Therapy to prevent blood clots (anticoagulation) in high-risk pregnant women with antibodies to phospholipids needs evaluation. Trials of more focused and effective anti-inflammatory therapy are also needed. More research is needed to elucidate the factors contributing to accelerated cardiovascular disease in patients with SLE.
Thrombotic Thrombocytopenic Purpura
Plasmapheresis has improved the survival of patients with thrombotic thrombocytopenic purpura (TTP), but it remains an expensive and laborious procedure. The metalloprotease ADAMTS 13 could be useful in the development of therapy for familial TTP. The expression and yield of recombinant ADAMTS 13 have limited large-scale production of the protease, which will be needed for clinical studies. A rapid and reliable assay suitable for clinical use to measure ADAMTS 13 activity is needed.