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Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1999

National Heart, Lung, and Blood Institute (NHLBI)

Overview of Rare Diseases Research Activities

NHLBI provides leadership for a national program in the causes, diagnosis, treatment, and prevention of diseases of the heart, blood vessels, lungs, and blood and sleep disorders and in the uses of blood and the management of blood resources. It conducts and supports, through research in its own laboratories and through extramural research grants and contracts, an integrated and coordinated program that includes basic investigations, clinical trials, epidemiological studies, and demonstration and education projects.

Although most of the research supported by NHLBI addresses common conditions such as hypertension, coronary heart disease, and chronic obstructive pulmonary disease, much research is devoted to rare diseases. NHLBI rare diseases research activities in FY 1999 are described below.

Recent Scientific Advances in Rare Diseases Research

Heart and Vascular Diseases Program

Antiphospholipid Syndrome

Patients with the antiphospholipid syndrome (APS) have circulating autoantibodies to certain phospholipids (lipids containing phosphorus), chiefly cardiolipin, and the lupus anticoagulant. APS manifests itself clinically by recurrent venous and arterial thrombosis, fetal deaths, and autoimmune thrombocytopenia. Many patients with APS have SLE, but patients may also have APS in the absence of lupus. An increased incidence of atherosclerosis further complicates the clinical picture. Functional genomics has brought new focus to the study of APS. Research is under way that will determine whether genetic factors predispose individuals to develop this unusual class of antibodies. Allelic variability in the genes for certain lipid carrier proteins is known to result in the generation of APS. NHLBI is supporting a study on the molecular genetics of one of these proteins, apolipoprotein H, in SLE patients to further understanding of the link between SLE and the production of antiphospholipid antibodies. Several NHLBI grantees are engaged in efforts to develop more standardized immunoassays that will reliably detect individual antiphospholipids. Recent findings provide strong support for the involvement of antiphospholipid antibodies in atherogenesis. Autoreactive antibodies were found to form against phospholipid components of dead or dying (apoptotic) cells and were then found to cross-react with normal vascular constituents that are produced in response to environmental stimuli including bacteria. In other studies, small differences in a common lipid carrier protein appeared to be genetically linked to APS and to atherosclerosis.

Arrhythmogenic Right Ventricular Dysplasias

Arrhythmogenic right ventricular dysplasias (ARVD) are a family of rare cardiomyopathies that result in sudden cardiac death (SCD) and malignant heart rhythm disturbances that lead to ventricular failure and cardiac fibrillation. Prevalence is unknown, but it is believed to be significant. Most forms of the condition seem to be due to inheritance of autosomal dominant mutations in genes whose identities remain unknown. Several chromosomal sites strongly associated with the disease have now been mapped. ARVD is characterized by marked, selective, right ventricular (RV) dilation; myocardial cell death and replacement by fat cells and fibrous tissue; and reduced RV outflow, in addition to any arrhythmogenic consequences. ARVD appears to be variably expressed, so people who inherit the disease may experience some or no symptoms at all. No therapies have proved effective. Currently, NHLBI supports no research directed exclusively at this condition, but staff are working with researchers to develop a series of collaborative grants that will attempt to identify some of the genes involved. Six genetic loci for ARVD have been mapped in Europe, where the disease was first recognized. Two additional loci have been mapped in two families with ARVD in North America. The most recent of these indicates that a gene for ARVD resides on chromosome 10. Chromosomal localization of the genes is an important first step in identifying the genetic and molecular defects responsible for the disease.

Bartter's Syndrome

Bartter's syndrome, a rare autosomal recessive disease, typically manifests itself through salt imbalance and low blood pressure. Previous studies showed that a mutation in the Na-K-2Cl cotransporter is responsible for this anomaly. One of the participating investigators in the NHLBI Molecular Genetics of Hypertension Specialized Centers of Research (SCOR) program has now discovered another cause. A mutation in an ATP-sensitive potassium channel also produces the syndrome. This new finding establishes the genetic heterogeneity of Birder syndrome and further demonstrates the physiological role of the associated potassium channel as a new important regulator of blood pressure and ion and fluid balance.

Brugada Syndrome

Brugada syndrome is an inherited disorder associated with the occurrence of sudden cardiac death (SCD) caused by unexpected onset of fibrillation (an extremely rapid ventricular heart rhythm) in patients without significant structural heart disease. It is characterized by a specific electrocardiographic (ECG) pattern referred to as right bundle branch block and by ST elevations in specific ECG leads. At least some forms of the syndrome are caused by mutations in the cardiac (sodium) ion channel responsible for initial polarization of the action potential. NHLBI supports several investigator-initiated research projects designed to elucidate the genetic and molecular defects responsible for the symptoms of Brugada syndrome. NHLBI also supports an international registry on the clinical and genetic characteristics of individuals affected by the disease.

Multiple mutations in the SCN5A gene associated with Brugada syndrome have been sequenced and their effects studied in vitro to determine the mechanisms involved in arrhythmia generation. These mutations appear to increase according to the magnitude of the inward current carried by sodium ions during initiation of each cardiac cycle. The relationship between Brugada syndrome and another set of inherited arrhythmias known to be a major cause of sleeping deaths in young Asian and Indonesian men is also being explored.

Congenital Heart Block in Neonatal Lupus Syndromes

Congenital heart block (CHB) in neonatal lupus syndromes is associated with abnormally slow heart rhythms (bradycardia) and other neonatal abnormalities affecting the skin, liver, and blood. During the neonatal period, 20% to 30% of the victims die. CHB is believed to result from transplacental passage of autoantibodies to soluble ribonucleoproteins from mothers with SLE. In the fetus, maternal antibodies produce an autoimmune response that results in damage to the atrioventricular (AV) node of the developing heart. After damage to this small region of the heart, children develop various degrees of AV block, a heart rhythm disturbance requiring artificial ventricular pacemaker implantation in about 60% of victims. NHLBI supports one investigator-initiated research project to determine the role of maternal autoantibodies in the pathogenesis of CHB. An antibody-specific animal model for CHB has been established in mice. Future data from this model may provide insights into the pathogenesis of CHB that would be useful in developing new therapies for its treatment and may aid understanding of congenital heart malformations in general.

Congenital Heart Disease

Congenital heart disease refers to abnormal formation of the fetal heart that results in structural heart defects and abnormal heart function. It is the most common birth defect, occurring in nearly 1% of newborns. Congenital heart disease is an important cause of infant mortality, pediatric and adult morbidity, and shortened adult life expectancy. NHLBI-supported researchers have made significant progress in understanding the molecular and genetic basis of normal and abnormal heart development. The outline of the complex pathway that specifies the different left and right sides of the heart is beginning to be filled in. Other studies have led to important insights into nutritional factors that affect heart development, including folate and the family of B vitamins. Innovative research continues to improve the likelihood that fetal surgery will be able to correct congenital heart defects. Researchers in NHLBI's Pediatric Cardiovascular Medicine SCOR program have identified several new genes and proteins responsible for normal and abnormal heart development, partly by using information from large families in which certain types of heart defects recur.

After early infancy, heart cells do not divide, so, unlike other organs, the ability of the heart to repair itself is limited. Researchers at the annual Weinstein Cardiovascular Development Conference held in May 1999 reported some success in getting certain types of premature cells to turn into heart muscle cells in the laboratory. Transplanting such cells into hearts may be a way to help failing hearts in children and adults. In addition, these cells may represent an ideal vehicle for delivering genes or gene products to diseased hearts.

At the same conference, an NHLBI-funded researcher made the first report of a gene thought to signal the endothelial cells that line the heart to become heart valve tissue. Because the heart valves are often abnormal in congenital heart disease, this may represent a significant advance in understanding of how normal valves form.


Dysbetalipoproteinemia is a disorder with a strong heritable component characterized by the presence of -migrating very low density lipoprotein. It leads to the formation of characteristic yellow skin plaque (xanthomas) and predisposes to early ischemic heart disease and peripheral vascular disease. NHLBI supports a program project addressing the genetics and biochemical events underlying the etiology and pathophysiology of the disease. In 1999, E2, a mutant form of the protein component apo-E, was found to be the primary molecular defect. Animal models with selective synthesis of apo-E variants are being produced to facilitate further studies. Investigations of remnant retention are continuing at several locations.

Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is transmitted in an autosomal dominant fashion. The disease is associated with myofibrillar disarray and leads to cardiac hypertrophy. Although patients are asymptomatic, the disease may lead to shortness of breath, palpitations, heart failure, or sudden death. Some individuals with the disease die during childhood, whereas others survive to the sixth or seventh decades. In addition, FHC is associated with mutations in various proteins, which suggests that FHC may not be a single disease but rather may represent a heterogeneous group of disorders. During the past decade, scientists have made significant progress in uncovering the genes associated with the disease. It is known, for instance, that FHC can be caused by many different mutations in contractile proteins that make up the heart wall. However, understanding who will die suddenly or whether certain factors, such as high blood pressure or extreme stress, will trigger sudden death remains elusive.

Several groups of geneticists and cardiologists have recently developed mouse and rabbit models of FHC that should greatly enhance genetic studies of the disease. NHLBI supports research on the genetic basis and mechanisms involved through several investigator-initiated grants and in two Heart Failure SCORs. These investigators have demonstrated that genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility. To elucidate the role of cardiac myosin-binding protein C (MyBP-C) in myocardial structure and function, investigators in one SCOR have produced mice expressing altered forms. Their studies revise current understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate its importance for long-term sarcomere function and normal cardiac morphology. In addition, mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in human beings.

Infectious Myocarditis

Infectious myocarditis, which affects both children and adults, is characterized by inflammation of heart muscle, sometimes leading to progressive heart failure and the need for heart transplantation. NHLBI supports grants that are investigating various aspects of myocardial inflammation, including virus-receptor interactions. One grantee has identified a receptor component that may be responsible for many of the clinical manifestations of myocarditis. In addition, one of NHLBI's MERIT awardees has demonstrated that anti-streptococcal antibodies that cross-react with cardiac myosin are cytotoxic to human endothelial cell lines, thus possibly establishing an explanation for the cellular and valvular damage seen in infectious myocarditis.

Liddle Syndrome

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's 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 identified by a prolonged QT segment on an electrocardiogram and is associated with syncope, ventricular arrhythmias, and, frequently, SCD. Studies have found that LQTS is often inherited and is related to mutations in membrane ion channels. In some forms of the disease, afflicted individuals may inherit other abnormalities, such as deafness, and have varied clinical outcomes depending on their specific mutational patterns. About 70% of diagnosed cases are in women.

NHLBI supports one Sudden Cardiac Death SCOR that addresses the molecular and genetic bases of LQTS. In addition, eight investigator-initiated research projects are attempting to elucidate the factors responsible for arrhythmia initiation in LQTS and the pharmacological and therapeutic interventions useful in its treatment. NHLBI also supports an International LQTS Registry that is used by investigators worldwide interested in the syndrome. A small clinical trial of gene-directed pharmacotherapy for the LQT3 variant of the disease has also recently begun.

Recent scrutiny of SCN5A, the gene encoding the cardiac sodium channel, in a large eight-generation family with a high incidence of nocturnal sudden death has led to discovery of a new, three-nucleotide mutation. This single mutation is associated with expression of one form of LQTS and Brugada syndrome, another rare disease also associated with life-threatening ventricular arrhythmias causing distinctive ECG changes that often result in SCD.

Niemann-Pick Disease Type C

Niemann-Pick disease type C (NPC) is an autosomal recessive lipid-storage disorder usually characterized by enlargement of the liver and spleen (hepatosplenomegaly) and severe progressive neurological dysfunction. Biochemical analyses of NPC cells suggest an impairment in the intracellular transport of cholesterol to postlysosomal destinations. The gene deficiency in Niemann-Pick disease types A and B has been identified as the acid sphingomyelinase. The gene deficiency in types C and D has been identified as the NPC-1 protein, but few clues regarding its potential function(s) have been derived from its predicted amino acid sequence. The accumulation of cholesterol in NPC results from an imbalance in the flow of cholesterol among membrane compartments. In 1999, a putative cholesterol sensor in the plasma membrane that affects cholesterol trafficking into and out of cells was characterized. The same investigators are also testing whether the cholesterol pool inside the cells is regulated by the plasma membrane sensor and whether the Golgi apparatus serves as an intermediary in cholesterol transport.

Smith-Lemli-Opitz Syndrome

The Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomal recessive disorder caused by a defect in the enzyme that catalyzes the last reaction in cholesterol biosynthesis. As a result, endogenous cholesterol synthesis is inadequate to meet biological demands for functions such as membrane structure and bile acid synthesis, and the precursor 7-dehydrocholesterol and its derivatives accumulate. Newborns with SLOS have a distinctive facial dysmorphism, they suffer from multiple congenital anomalies (including cleft palate, congenital heart disease, genitourinary abnormalities, and malformed limbs), and exhibit severe developmental delays, digestive difficulties, and behavioral problems. The syndrome is thought to account for many previously unexplained cases of mental retardation. NHLBI-supported research in SLOS is focusing on identification of relevant mutations, generation of animal models, development of sensitive and specific assays for screening of newborns and verification of diagnoses in older individuals, clarification of aberrant biochemical pathways, and amelioration of behavioral and digestive problems through dietary and pharmacological treatment.

Tangier Disease

Tangier disease is a rare syndrome characterized by a deficiency in high-density lipoprotein (HDL), mild hypertriglyceridemia, neurological abnormalities, and massive cholesterol ester deposits in various tissues such as the tonsils. Cells from Tangier disease patients have a defect in intracellular lipid trafficking preventing the removal of cholesterol from the cells. A member of the ATP-binding cassette (ABC) transporter family, human ABC-1, located on chromosome 9, was identified in 1999 as the defective gene in Tangier disease, thus opening new avenues of research into the mechanisms involved in intracellular cholesterol trafficking.

Lung Diseases Program

alpha symbol1-Antitrypsin (AAT) Deficiency

alpha symbol1-Antitrypsin (AAT) deficiency is an inherited deficiency of a circulating proteinase inhibitor that is manufactured primarily in the liver. Deficiency states (circulating serum AAT levels less than 0.6 mg/ml) are associated with emphysema, presumably from inadequate protection against enzymatic destruction by neutrophil elastase. Fifteen percent of the AAT-deficient population also develops liver disease.

NHLBI funds various clinical and basic research projects on AAT deficiency. This research includes the study of the molecular mechanisms that impair secretion of AAT; inherited traits or environmental factors that exaggerate the accumulation of AAT or response to it; methods of gene therapy delivery; personality, coping styles, and quality of life of AAT patients; and ways to increase availability of defective but partially active AAT. In addition to the research that specifically focuses on AAT, NHLBI supports several grants for the study of similar enzymes (their function, synthesis, secretion, and interaction), animal models of other enzyme deficiencies, gene regulation, gene therapy, and cellular transport, signaling, injury, and repair. This research will contribute to understanding of AAT deficiency and provide new approaches to therapy. The Institute also continues to support an AAT patient registry; results from the registry will soon be submitted for publication.

Investigators continue to work on defining the abnormalities in the protein, its degradation, and associated inflammation that lead to disease in various AAT deficiency states. New therapies in the early stage of study include enhancement of the partially active mutant protein transport through the liver.

Bronchopulmonary Dysplasia

Approximately 30% of the increasing number of very low birth weight infants who are surviving prematurity develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disordered lung growth, i.e., alterations in cell size and shape and decreased numbers of alveoli available for gas exchange. BPD is regarded as a disorder in which the physiological consequences of in utero distress, such as infection or inflammation, alter the pattern of subsequent lung development. These changes, in turn, influence the ability of the immature lung to respond to the stresses encountered in the transition to an oxygen-rich environment at birth. Studies on cytokine interactions and growth factor antagonists in models of aberrant lung development indicate that a disturbance in the complex, normal biochemical cascade that affects lung development determines the maturity of the lung at birth and its potential developmental capacity beyond. NHLBI supports a basic research program on the molecular development of the lung with a view to identifying opportunities for possible interventions to prevent BPD. As a result, a complex cascade of interactions is beginning to emerge concerning the temporal and spatial signals that regulate lung development. In addition, NHLBI supports investigations on a molecular characterization of BPD developed in a uniform, nonhuman primate model of the disease.

Recently, the accumulation of two markers, 3-nitrotyrosine in plasma and bombesin-like peptides (BLPs) in urine, have been identified as possible predictors of the development of BPD in very low birth weight premature infants. Data indicate that postnatal administration of blocking anti-BLP antibody is protective against the development of clinical and pathological evidence of BPD. In addition, dilation of pulmonary vessels with inhaled low-dose NO has been observed to reverse some of the deleterious lung remodeling characteristic of BPD. A current hypothesis is that NO can decrease the regional hypoxemia created by the inflammatory component of BPD. Nitrotyrosine levels, used to monitor the production of oxygen radical species, were consistent with the safety of short-term use of NO therapy. A multicenter clinical trial was planned to determine whether low-dose inhaled NO administered to preterm infants who require mechanical ventilation at 10 days will increase survival without chronic lung disease at 36 weeks postmenstrual age.

Cystic Fibrosis

Cystic fibrosis (CF) is a multisystem disease characterized by defective transport of chloride and sodium across the cell membrane. It is the Nation's number one genetic cause of death of children and young adults. Ninety percent of people with CF die from pulmonary complications. More than 25,000 Americans have CF, with an incidence of about 1 in 3,300 among whites. The responsible gene, the CF transmembrane conductance regulator (CFTR), was identified in 1989. More than 800 mutations and DNA sequence variations identified in the CFTR gene contribute to a highly variable presentation and course of the disease. NHLBI supports a vigorous program of basic, clinical, and behavioral research in CF. Research is focused on the etiology, pathophysiology, and treatment of CF and, specifically, on how they relate to the pulmonary manifestations that are the major causes of morbidity and mortality in CF.

The effectiveness and safety of long-term antibacterial therapy delivered directly to the airways was evaluated to determine whether this regimen would help maintain pulmonary function. The results of two placebo-controlled, multicenter, randomized, double-blind trials on the efficacy and safety of intermittent administration of inhaled tobramycin in patients with CF and Pseudomonas aeruginosa infection demonstrate that long-term use of inhaled tobramycin preserves lung function, reduces lung colonization by the microorganism, and decreases the risk of hospitalization. Active treatment was not associated with toxicity and was well tolerated.

Recent studies have shown that in vitro and in vivo gene transfer to airway epithelia can be significantly enhanced by including the viral vector in a calcium phosphate coprecipitate to increase binding of virus to cell. Modification of host barrier properties with surface-active agents and/or membrane-perturbing agents, synthetic or naturally derived, has been shown to provide another novel approach to enhancing the efficiency of in vivo airway gene transfer. Moreover, transient disruption of the integrity of tight junctions between neighboring cells has been shown to allow greater access of the viral vector to the basolateral surface of epithelial cells where viral receptors are located, thereby facilitating more efficient interaction and entry by the virus.

Antimicrobial peptides may play a role in airway host defense against microorganisms. CF patients are unable to eliminate pathogenic bacteria from the surface of their airways. A novel genetic strategy for reversing this CF-specific defect of antimicrobial activity by overexpression of an endogenous broad-spectrum antibiotic (cathelicidin) demonstrated restoration of bacterial killing activity. These findings support the role of antimicrobial peptides in host defense against bacterial infection.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF), a disease in which functioning healthy lung tissue is replaced by nonfunctional connective tissue that contains fibroblasts and collagen, is initiated by unidentified causes. It is commonly treated with corticosteroids, sometimes in combination with other potent drugs, and less commonly with lung transplantation. Therapy is rarely effective, and the disease progresses to result in death over a relatively short time in most patients. Recent estimates put the prevalence at 185,000 and the incidence at 70,000. NHLBI-supported research is continuing on the molecular and cellular events that trigger the inflammation of alveoli seen in the early stage of idiopathic pulmonary fibrosis and influence its progression to the irreversible, fibrotic, end stage. In FY 1999 pirfenidone was found to protect against pulmonary fibrosis in an animal model by preventing synthesis of growth factors by alveolar macrophages. Also, interstitial pulmonary macrophages were found to be a source of insulinlike growth factor I, which has been implicated in the pathogenesis of IPF through its ability to stimulate fibroblast proliferation and collagen synthesis. The NHLBI intramural program is conducting three observational clinical research protocols of subjects with familial and nonfamilial forms of IPF in collaboration with Boston University, Johns Hopkins University, and INOVA Transplant Center.


Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects women, usually during their reproductive years. Symptoms develop as the result of proliferation of atypical, nonmalignant smooth muscle cells in the lungs. Diagnosis is usually made by lung biopsy. 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 variable but usually slowly progressive, eventually resulting in death from respiratory failure. Although no treatment has proved effective in halting or reversing LAM, lung transplantation is a valuable treatment for patients with end-stage lung disease. Some patients with tuberous sclerosis complex (TSC), a genetically transmitted disease, develop lung lesions identical to those seen in LAM. In some cases, the clinical distinction between TSC and LAM may be difficult.

NHLBI supports research on LAM in both its intramural and extramural programs. As part of the intramural program, the Institute has established a research laboratory at the NIH Clinical Center to learn more about the cause and progression of LAM at the clinical, cellular, and molecular levels. Researchers are determining the characteristics of the unusual smooth muscle cells that damage the lungs of LAM patients. An important aspect of the research is learning how growth is regulated in these cells.

The NHLBI extramural program supports a national LAM Patient Registry that is coordinated by the Cleveland Clinic Foundation. The Office of Research on Women's Health cofunds the registry with NHLBI. Patients can be enrolled through six major participating Centers (the NIH Clinical Center is one of the sites) or by a patient's personal physician. The LAM Registry began enrolling patients in the summer of 1998. As of April 2000, 165 LAM patients had begun the enrollment process.

During 1999, progress was made in understanding the genetic mechanisms leading to smooth muscle proliferation in LAM and the relationship between LAM and TSC. TSC is an inherited disorder, and LAM is a disease that occurs sporadically (does not appear to run in families). One NHLBI-supported investigator is examining genetic mutations found in cells taken from the lungs and kidneys of LAM patients to determine how the two disorders (TSC and LAM) are linked. This research may lead to new diagnostic and therapeutic strategies for women with LAM.

In other scientific advances of note, an immunohistochemical analysis suggests that the production of proteins that inhibit cell death in LAM cells may be controlled by hormones. This may be a clue to understanding the imbalance that causes overgrowth of these cells. Two clinical reviews of LAM were published in 1999 in the journal Chest.

The NHLBI intramural program has published findings regarding cell markers for LAM and the cell proteins associated with hormone receptors on LAM cells. Earlier, the group had discovered that the hallmark of LAM cells is that they react with a monoclonal antibody, HMB45, that recognizes a protein that is also found in human melanoma cells. More recently, it was learned that, within LAM tissue, HMB45 binds to cytoplasmic granules in large epitheliod cells. Another marker that indicates cellular proliferation, PCNA, appears in spindle-shaped cells. An inverse relationship exists between the two markers in the LAM and melanoma cells. LAM cells with a significant amount of PCNA reactivity and a small amount of HMB45 reactivity may be more important in LAM progression than those that react strongly with HMB45.

Persistent Pulmonary Hypertension of the Newborn

Approximately 1 in 1,000 live term births is associated with persistent pulmonary hypertension of the newborn (PPHN). Affected newborns are poorly oxygenated because their lung arteries fail to dilate after birth to allow for normal blood flow to the lungs. They require costly and prolonged medical care including airway intubation, inhalation of 100% oxygen, mechanical ventilation, and, often, heart/lung bypass (extracorporeal membrane oxygenation). Two of the five NHLBI Pathobiology of Lung Development SCORs, established to facilitate transfer of research findings to the clinic, are currently focused on PPHN. In addition, a clinical study is addressing maternal risk factors that may influence PPHN incidence in term infants, an aspect of PPHN that has been debated for several years.

NO is an experimental therapy that offers promise for less invasive treatment of PPHN. Recent studies point to a critical role for NO as a modulator of levels of endogenous vasoactive mediators whose net balance determines pulmonary vascular tone and vessel wall structure. NO regulates both endothelin (a potent vasoconstrictor) and vascular endothelial growth factor (VEGF) production, potentially leading to alterations in vascular tone and permeability. Understanding the molecular mechanisms by which NO regulates gene expression under hypoxic conditions and the role it may play in modifying the vascular responses has widespread implications for the treatment of PPHN.

Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD), otherwise known as Kartagener's or immobile ciliary syndrome, is an inherited disease characterized by ultrastructural defects in the cilia lining the respiratory tract, resulting in impaired ciliary function, reduced or absent mucociliary clearance, and susceptibility to chronic, recurrent respiratory infections, including sinusitis, bronchitis, and pneumonia and usually accompanied by otitis media. Many patients experience hearing loss. Male infertility is common. Situs inversus occurs in approximately 50% of PCD patients. Clinical progression of the disease is variable; in severe cases, lung transplantation is required. For most patients, aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections are recommended. Although the true incidence of the disease is unknown, it is estimated to be 1 in 32,000 or higher. A diagnosis of PCD is based on documentation of ultrastructural abnormalities of the cilia at the EM level and/or videomicroscopic analysis of ciliary function. PCD is a genetically heterogeneous disease in which family studies support an autosomal recessive pattern of inheritance.

Although PCD has been the focus of many scientific investigations, little progress has been made in identifying its genetic cause. Recent advances in the areas of protein biochemistry and cell culture of airway epithelial cells could enable new insight into the genetic basis of PCD and increase understanding of its pathogenesis. An NHLBI-supported study is seeking to identify defects in the cilia of PCD patients at the level of individual proteins and, ultimately, mutations responsible for some cases of PCD. The results of the studies may increase understanding of ciliary structure and function and lead to improved diagnosis and clinical outcomes for patients with PCD and other respiratory diseases.

Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is a rare, progressive lung disorder for which there is no cure. It is characterized by a sustained elevation in pulmonary arterial pressure. This is associated with structural changes in the small pulmonary arteries, resulting in resistance to blood flow. The process eventually leads to an enlarged, overworked right ventricle that is unable to pump enough blood to the lungs, resulting in heart failure and death, usually within 3 to 5 years of the initial diagnosis. Estimates of the incidence of PPH range from 1 to 2 people per million in the general public, with women being predominantly affected. Approximately 6% of PPH cases are due to familial PPH. The familial form is inherited as an autosomal dominant trait that has been localized to a region on chromosome 2. Although medical treatment for PPH has improved over the past decade, no therapeutic approach is uniformly accepted or successful.

NHLBI supports basic research on the cellular and molecular events underlying the pathogenesis of PPH. The following are dominant themes of PPH research:

  1. Gaining better understanding of the structural aspects of the disease that cause proliferative and obliterative changes of the vasculature.
  2. Identifying genes that affect functional changes in the pulmonary vasculature.
  3. Identifying and evaluating more effective treatments.
  4. Isolating the familial PPH gene.

Investigators have demonstrated that the endothelial cells lining the blood vessels in patients with PPH have an abnormal growth pattern similar to that seen in the neoplastic process. A three-dimensional computer model, used to reconstruct the vascular layers of the altered vessels in PPH patients, has demonstrated that the growth of the lesions may depend on different types of endothelial cells comprising the lesions, which may be in different stages of maturity and differentiation.

Continuous intravenous infusion of prostacyclin is the most effective therapy for PPH, to date; however, the mechanisms involved in its effectiveness are unknown. Transgenic and knockout animal models have been generated for the genes that are involved in prostacyclin signaling to examine physiological responses. In a mouse model that overproduces the enzyme needed for prostacyclin synthesis, the mice were protected from developing pulmonary hypertension in response to hypoxia. Other studies have suggested that prostacyclin functions by altering the levels of the vasoconstrictor endothelin-1.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of lipoproteinaceous material within the alveoli. The congenital form of the disease is fatal and occurs in 1 in 100,000 live births. The pathophysiological basis of congenital PAP is associated with mutation in the gene for surfactant protein B, leading to synthesis of inadequate quantities of normally functioning surfactant protein B. The cause of adult-onset PAP is not well characterized and may be associated with the heterozygous condition for mutation in SP-B and deficiency of GM-CSF or may occur in association with various conditions including silicosis and certain types of malignancies. NHLBI supports investigator-initiated studies to define the molecular basis for PAP development and to determine the incidence of the mutations responsible for congenital PAP. Molecular analysis of cord blood specimens, reserved by various state health departments and abroad as components of birth/death certificate data, is being done to determine the frequency of relevant SP-B mutations among varied ethnic populations.

In 1999, deletion of the gene encoding GM-CSF in mice was found to result in progressive accumulation of surfactantlike material in the distal air spaces, with the pathological findings resembling the histology seen in human PAP. In GM-CSF-deficient mice treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4 to 5 weeks, lung histology, alveolar macrophage differentiation, and surfactant B immunostaining returned toward normal, and alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased. Cessation of treatment resulted in return to pretreatment concentrations. Systemic administration of GM-CSF to the mouse model of PAP had no effect. In another significant finding, molecular analysis of genomic DNA revealed at least two mutations associated with fatal congenital PAP, the "common" 121ins2 mutation in exon 4 and a novel 2bp frameshift mutation in exon 5.


Sarcoidosis is a chronic multisystem disease of unknown cause in which affected organs, especially the lungs (the most common site of disease activity), are invaded by different types of inflammatory cells that become organized into clusters of cells called granulomas. Sarcoidosis affects people of all ages, sexes, and races, although higher incidences are reported for young adults and African Americans. The illness can be self-limited or chronic, with episodic outbursts and remissions. In some patients, the disease is characterized by a chronic interstitial pneumonitis, accompanied by progressive deterioration of lung function associated with scarring, fibrosis, and permanent destruction of lung tissue. The estimated number of patients with sarcoidosis ranges from 13,000 to 130,000, with 2,600 to 27,000 new cases each year. The NHLBI intramural research program has initiated a randomized, double-blind, placebo-controlled clinical protocol to determine whether pentoxifylline, a xanthine derivative that has been used for many years in the treatment of peripheral vascular disease, can be beneficial as an adjunct to corticosteroid therapy in patients with pulmonary sarcoidosis.

Blood Diseases and Resources Programs

Acute Graft Versus Host Disease

GVHD is a condition that typically occurs within 3 months after allogeneic hematopoietic stem cell or marrow transplantation in which donor T cells react against disparate recipient histocompatibility antigens. It is characterized by skin rash, liver dysfunction, and diarrhea. NHLBI supports basic and clinical research grants focused on understanding the pathophysiology GVHD, especially in unrelated transplants. The program emphasizes understanding of the roles of both major and minor histocompatibility antigens in disease pathogenesis, development of tolerance, function of donor T cells in allogeneic hosts, and mechanisms of GVHD prevention, including depletion of donor T cells from the graft. In 1999, NHLBI-supported research group showed that different types of mouse T cells can induce or suppress GVHD. The cell types can be distinguished by the cytokines they produce. The significance of this finding is that manipulation of these subsets might lead to control of GVHD. Other studies have reported on various approaches to the blocking of cytokines and their receptors. The results hold promise for ameliorating GVHD.

Cooley's Anemia

Cooley's anemia (also called beta symbol-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 time and eventually becomes toxic to tissues and organ systems.

In 1999, NHLBI grantees used a -globin gene/ -locus control region retroviral vector to optimize gene transfer and expression in a mouse transplant model. The results demonstrate high-level, long-term somatic human -globin gene transfer into the hematopoietic stem cell of an animal and suggest the possibility of a retroviral gene therapy approach to sickle cell disease and the beta symbol-thalassemia. New methods of transfusion therapies and less toxic methods of stem cell transplantation are being developed that may be used for patients with beta symbol-thalassemia.

Fanconi Anemia

Fanconi anemia (FA) is an autosomal recessive bone marrow failure syndrome characterized by a decrease in blood cells and platelets (pancytopenia), developmental defects, and cancer susceptibility. Many FA patients can be identified at birth because of congenital anomalies, although approximately 25% do not have birth defects. FA is a clinically heterogeneous disorder that can currently be divided into at least eight different complementation groups, designated A through G. Two FA genes, FAC and FAA, have been cloned that together account for an estimated 75% of all FA patients worldwide. So far, eight distinct complementation groups (designated FAA-FAG) have been reported, suggesting that at least eight genes are involved in the manifestations of FA. Several studies are in progress that define the FA complex of proteins and provide insight into the potential function. Recent transplantation protocols with fludarabine have provided new hope that stem cell transplantation may be a therapeutic option for patients with FA.

Sickle Cell Anemia

Sickle cell anemia is an inherited disease that is most common among people whose ancestors come from Africa, the Middle East, the Mediterranean basin, and India. In the United States, it affects primarily African Americans, about 72,000 of whom have the disease. Sickle cell disease is the most common genetic blood disorder in the United States, affecting approximately 1 in 500 African-American newborns and 1 in 1,000 Hispanic newborns each year. It occurs when an infant inherits the gene for the sickle hemoglobin from both parents (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 -thalassemia). One in 12 African Americans carries the sickle cell trait (Hb AS). In patients with the disease, the hemoglobin molecules in the red blood cells that carry oxygen throughout the body tend to damage the red cell walls, causing them to stick to blood vessel walls. This leads to the sickle cell crises or painful episodes that are the hallmark of the disease. Chronic end-organ damage occurs to the brain, lungs, kidneys, spleen, and liver and leads to premature death, with the median age at death for severely affected individuals being 42 to 48 years.

In December 1998, an unrelated cord blood transplant was performed on a 12-year-old boy with sickle cell anemia who had a history of stroke treated with chronic blood transfusions since age 5. The patient developed GVHD which involved his liver and his intestines, and required frequent hospitalizations and immunosuppressive therapy. The boy's bone marrow now appears to be producing normal hemoglobin, with no sign of sickle hemoglobin. This case provides grounds for cautious optimism that alternative sources of bone marrow stem cells may exist to treat hemoglobinopathies. Currently, related bone marrow donors are sought for children with sickle cell disease who are referred for bone marrow transplantation. Given that less well matched transplants may be possible with cord blood, an increase in the estimated 18% of children with compatible sibling donors may make bone marrow transplantation a more common therapeutic option in the future for children with severe sickle cell disease.


Hemophilia is a hereditary bleeding disorder that results from a deficiency in either blood coagulation factor VIII or factor IX. About 20,000 individuals with hemophilia in the United States are dependent on lifelong treatment to control periodic bleeding episodes. In 1999, gene therapy studies by NHLBI-supported scientists showed sustained expression of factor IX in mice and hemophilic dogs after muscle injection of AAV vector expressing factor IX. Early reports of the first phase I clinical study for factor IX gene therapy give evidence for gene transfer and protein expression in hemophilia B patients treated with the factor IX-expressing AAV vector. A mouse model for antibody inhibitor formation was developed in a hemophilia A mouse, and the immune response was found to be T-cell dependent. The studies suggest that drugs targeting the B7-CD28 pathway may be potential therapies to prevent and treat inhibitory antibodies.

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder resulting from weakness of the vascular support structure. Its most common manifestations are red spots on the lips and bleeding from mucosal membranes such as those in the nose. Advanced stages, often present with arteriovenous malformations in the lung, brain, gut, and liver. Two gene defects have been identified in patients with HHT: one is in the 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. NHLBI supports a broad spectrum of research in hemostasis and thrombosis that is partly focused on understanding the biology of platelet activation, the mechanism of clotting, and the interaction of blood with the vascular surface. The underlying molecular basis of HHT has been determined and appears to be a defect in any component of the TGF- -receptor complex on the endothelial cell. The type I receptor (Alk-1) and the type III receptor (endoglin) have been identified, but the type II receptor remains unknown. Eight mutations in endoglin leading to HHT have been identified, and a database on genetic mutations related to HHT has been established.

Systemic Lupus Erythematosus

SLE is an autoimmune disorder in which the body produces antibodies that harm its own cells and tissues. Typical symptoms of SLE are fatigue, arthritis, fever, skin rashes, and kidney problems. Lupus affects more women than men. Patients with SLE have a higher incidence of thrombosis and spontaneous loss of pregnancy. Its cause is unknown, and there is no known cure. However, the symptoms can be controlled with appropriate treatment, and most patients can lead an active life. Recent studies suggest that circulating antibodies compete with a protein, annexin V, that forms an antithrombotic shield in the placenta in pregnant patients with SLE. Procoagulant phospholipids remain exposed and cause thrombosis in the vessels of the placenta, leading to loss of the fetus.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) can potentially be a fatal disease. It is characterized by low blood platelet levels and widespread platelet thrombi in arterioles and capillaries. Relapse is not uncommon in those who survive the acute phase. Both endothelial cell damage and intravascular platelet aggregation have been suggested in the pathogenesis of TTP. Microscopic examination of the thrombi has revealed the presence of abundant von Willebrand factor (vWf). Despite advances in basic sciences, treatment options and mortality associated with TTP remain unacceptable. NHLBI supports a broad spectrum of research in hemostasis and thrombosis that includes studies on the biology of platelet function, the mechanism of blood coagulation, and the interaction of blood with the vascular surface. An interaction between the plasma protein, vWf, and the platelet surface glycoprotein complex I (GP I) is believed to be essential for the formation of a thrombus. vWf is synthesized as large polymers and is then cleaved into smaller units by a plasma protease. The presence of inhibitory antibodies to the protease was confirmed in 1999 in some patients with TTP. Inhibition of the protease results in large amounts of vWf in plasma that can spontaneously aggregate platelets. Understanding the biosynthesis and processing of vWf may offer an opportunity to develop new treatment for TTP.

Rare Diseases Research Initiatives

Ongoing Initiatives Related to Rare Diseases

The following are ongoing initiatives of NHLBI:

  • Adult Hydroxyurea Patient Followup Study (or Multicenter Study of Hydroxyurea in Sickle Cell Anemia [MSH] Patients' Followup)
  • Behavioral Interventions for the Control of Tuberculosis
  • Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension (PPH)
  • Chronic Fatigue Syndrome Pathophysiology
  • Clinical Research on Cooley's Anemia
  • Clinical Networks for the Treatment of ARDS
  • Comprehensive Sickle Cell Centers
  • Gene Therapy for Hemophilias A and B
  • Gene Therapy for Sickle Cell Disease
  • Hematopoietic Stem Cell Biology: Basic Research
  • HIV-Associated Pathogens of the Lung: Life Cycle Regulation
  • Homocyst(e)inemia and Atherosclerosis
  • Human Stem Cell Sources Immunogenetics of Inhibitor Formation in Hemophilia
  • Lung-Specific Drug Delivery Systems for Tuberculosis (TB) Treatment
  • Mechanisms of Post-Bone Marrow Transplantation Lung Injury
  • Mitochondrial DNA Mutations in Heart, Lung, and Blood Diseases
  • National Gene Vector Laboratories
  • Pathogenesis and Treatment of Cystic Fibrosis
  • Sickle Cell Disease Therapy
  • Specialized Centers of Research (SCORs) in Hematopoietic Stem Cell Biology
  • Specialized Centers of Research (SCORs) in Neurobiology of Sleep and Sleep Apnea, Airway
  • Biology and Pathogenesis of Cystic Fibrosis, and Acute Lung Injury
  • Specialized Centers of Research (SCORs) in Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma
  • T-Cell Depletion of Marrow for Unrelated Bone Marrow Transplantation: Clinical Trial to Ascertain Risk:Benefit Ratio
  • Thrombocytopenia: Pathogenesis and Treatment
  • Tuberculosis Academic Award
  • Vascular and Hematopoietic Development and Disease

Initiatives Begun in FY 1999

Assay Methods Development for Creutzfeldt-Jakob Disease

A new RFA will develop assay methods for the detection of Creutzfeldt-Jakob Disease (CJD), a disease that, along with other transmissible spongiform encephalopathies, has not been studied seriously because of the lack of a satisfactory assay system. The immediate goal of the program is development of an assay to screen donated blood and donors of organs or tissues, although other uses of the technique are probable. Serologic, virologic, physical, and physicochemical approaches might be considered for mass screening for the hallmark abnormal isoform (PRP-res) or other potential markers for CJD.

Development of a Capsid Antigen-Based Parvovirus B19 Vaccine

A new Cooperative Research and Development Agreement (CRADA) will provide preclinical and clinical data needed to develop a safe and effective vaccine based on viral capsid antigen for the treatment of several conditions linked to parvovirus B19, including miscarriages in pregnant women, life-threatening sudden reduction in red blood cells (transient aplastic crisis) in sickle cell anemia patients, chronic anemia in AIDS and chemotherapy patients, and persistent or acute arthritis in some adults. No vaccines exist for the prevention of parvovirus B19 infection. The vaccine may also be useful in treating conditions such as childhood myocarditis, some neuropathic disorders, some vasculitis, fulminant hepatitis, and rheumatoid arthritis.

Developmental Processes in Differential Expression of Globin Genes

A new joint Program Announcement (PA) with NIDDK provides for the pursuit of basic investigations into the developmental processes involved in the differential expression of globin genes. It is designed to support research to elucidate mutations in the globin gene cluster that cause some of the most common inherited diseases in humans, such as sickle cell anemia and beta symbol thalassemia ( Cooley's anemia). Current treatment for these disorders includes both pharmaceutical agents and gene therapy. However, not all patients respond to the pharmaceutical agents, their applicability to other disorders is not established, and the molecular and cellular basis for their mode of action remains unclear. In addition, studies of the developmental and tissue-specific control of the globin gene cluster are important for optimizing gene transfer, via viral or chemical vectors, for gene replacement therapy. This PA is intended to promote the further advances needed to broaden the range of therapeutic strategies for disorders of globin synthesis.

Environment-Infection-Gene Interactions in Autoimmune Disease

A new trans-NIH RFA provides for determining the role of environmental and infectious agents in the initiation and/or exacerbation of autoimmune diseases. Innovative investigator-initiated basic or population-based studies were sought to elucidate

The role of exposure to environmental and/or infectious agents in the development of autoimmune diseases, including timing of exposure;
The role of genetic factors in modulating induction or perpetuation of autoimmune diseases by environmental or infectious agents; and/or
The interaction of hormones and gender differences with environmental or infectious agents in the development of autoimmune diseases.

The Exploratory Research Grant (R21) award mechanism used supports high-risk, high-payoff activities for which a traditional historical basis or preliminary data are lacking. Research fostered by these awards should lead to the development of more extensive hypothesis-driven mechanistically oriented research projects. One grant was supported by NHLBI under this RFA to study Innate Immunity in Virus-Induced Autoimmune Myocarditis.

FANCA Interaction with BRG-1

A new CRADA provides for determining whether BRG-1, a protein involved in chromatin modeling, interacts with FANCA, one of the genes that causes Fanconi's anemia.

Feasibility Studies of Retinoid Treatment in Emphysema

A new Broad Agency Announcement provides for determining the feasibility of conducting a randomized, controlled trial on the efficacy of retinoic acid, a derivative of vitamin A, in the treatment of emphysema. Under this Broad Agency Announcement research contract program, several small trials in different populations, with different agents and doses and using various outcomes, are to be conducted at four or five clinical centers and a data coordinating center. Secondary objectives are to identify optimal patient populations, drugs, dosing schedules, and outcome measures-either for a larger study, if indicated, or for treatment recommendations. This initiative could also have an impact on patients with the rare disease alpha symbol1-antitrypsin (AAT) deficiency.

SCORs in Pediatric Cardiovascular Disease

The renewal of an RFA provides for fostering interdisciplinary studies of the etiology, pathophysiology, and diagnosis of congenital and acquired cardiovascular disease in children in a context that will lead to more effective methods of treatment and prevention. The goals of the program are to encourage

Exploitation of the latest techniques of developmental and molecular biology and cellular and organ physiology to elucidate the underlying mechanisms that are perturbed in pediatric cardiovascular disease states.

Application of fundamental knowledge and modern technology to improve diagnosis, treatment, and prevention of these diseases.

Stem Cell Transplantation to Establish Allochimerism

A new RFA provides for developing improved preparative regimens that will permit incompatible hematopoietic stem cell transplantation in immunized recipients with hemoglobinopathies such as sickle cell disease and Cooley's anemia. Research supported under this initiative will explore the possibility of performing successful stem cell transplantation for hemoglobinopathies when complete destruction of the bone marrow (myeloablation) is not desirable and partial replacement of defective marrow may be sufficient for clinical benefit. The overall goal of the initiative is to enable successful stem cell transplantation for hemoglobinopathies and minimize recipient morbidity and mortality. Proposed approaches must have the potential to evolve into human clinical studies.

Strategies to Augment Alveolization

A new RFA provides for defining the critical processes that direct formation and functional differentiation of lung alveoli and determine whether similar principles apply to the induction of alveolar regeneration. Recent progress in developmental biology has opened new opportunities to expand the study of morphogenesis to the molecular level. The information generated by a full exploration of the genetic, cellular, and molecular mechanisms regulating alveolar formation should ultimately lead to rational interventions for aberrant development of the lungs, lung injury, and diseases such as emphysema, diffuse interstitial fibrosis, and BPD.

Initiatives Planned for the Future

Beryllium-Induced Diseases

A new interagency PA will encourage support of scientific projects on the cellular and molecular events that underlie the transition from antigen sensitization to beryllium to chronic beryllium disease to improve identification of markers of disease initiation and progression for early therapeutic intervention and effective environmental control strategies. The major source of beryllium emission into the environment is the combustion of fossil fuels, primarily coal, which releases beryllium-containing particulates and fly ash. The most significant exposure to beryllium occurs in occupational settings. Workers engaged in primary production, metal machining, and reclaiming scrap alloys are potentially exposed. In chronic disease, the alveoli contain small interstitial granulomata that resemble those seen in sarcoidosis. As the disease progresses, the granulomas become organized and eventually form small, fibrous nodules, and progressive impairment of pulmonary function occurs.

Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension

A PA continues important research in PPH, with an emphasis on stimulating research to elucidate a mechanistic understanding of the disease. Further studies are encouraged that address mechanisms involved, at the cellular and molecular level, in pulmonary vascular remodeling, pulmonary vascular tone, and the genetic basis of PPH. Research to identify novel genes or vasoactive mediators important in PPH pathology and determination of their functional effects on pulmonary vascular cells, the extracellular matrix, and pulmonary vascular tone is a high priority. Furthermore, research integrating the relationship between mediators of vasoconstriction and pulmonary vascular remodeling is strongly encouraged. The ultimate goal is to develop new and effective therapies.

Pediatric Heart Disease Clinical Research Network

A new RFA will establish a network of interactive pediatric clinical research centers to promote the efficient evaluation of new treatment methods and management strategies that have potential benefit for children with structural congenital heart disease, inflammatory heart disease, heart muscle disease, and arrhythmias. Therapeutic trials and studies may involve investigational drugs and drugs already approved but not currently used, as well as devices, interventional procedures, and surgical techniques. The network, consisting of six clinical centers and a data coordinating center, is expected to promote rapid dissemination of its findings to the medical community.

Programs of Excellence in Gene Therapy

A new RFA will establish up to five comprehensive Programs of Excellence in Gene Therapy (PEGT) to create multidisciplinary, collaborative research environments that promote rapid translation of basic, preclinical studies of gene therapy for cardiovascular, pulmonary, and/or hematologic diseases into human pilot experiments. The programs, supported by the U01 cooperative agreement grant mechanism, will provide shared access to specialized services such as preclinical toxicology testing, generation of vectors for preclinical and clinical use, large-scale production of biological reagents (e.g., cytokines), and biostatistical support. In addition, the programs will provide training to NHLBI-supported physician-scientists in translational (basic science to clinical application) research for gene therapy. Each program would have a minimum of two clinical projects under way at any one time and four to six training positions. One PEGT will serve as the Coordinating and Data Core. A one-time competitive renewal, for the existing awardees, may be accepted for an additional 5 years, for a maximum of 10 years of support.

Specialized Centers of Research in Hematopoietic Stem Cell Biology

An RFA extends for a second 5-year period the SCOR program to advance knowledge of basic stem cell biology in areas of stem cell isolation, quantitation by in vivo assay, in vitro and in vivo growth and expansion, gene insertion and long-term expression, and engraftment. Results will be applied clinically in efforts to achieve successful hematopoietic stem cell therapy to cure both genetic and acquired diseases and to perform successful gene therapy by using the hematopoietic stem cell as the target for gene transfection and for lifelong expression of normal genes. The SCOR mechanism is uniquely designed to support a spectrum of multidisciplinary basic and clinical research in a synergistic fashion that will enable major therapeutic advances in both gene therapy and stem cell transplantation to be realized in the next decade.

Rare Diseases-Related Program Activities

Workshops, Symposia, and Meetings

Workshop: Genetic Elements of Sudden Cardiac Death and Lethal Arrhythmias: Unknown Influences Within Populations

Workshop: Therapies for alpha symbol1-Antitrypsin (AAT) Deficiency
Cosponsors: The Alpha One Foundation and the ORD
Outcomes: The workshop recommended the following:

  • Initiation of collaborative research efforts.
  • Further investigations of inflammatory processes in the lungs.
  • Identification of the need for improved biological markers of lung inflammation and their use as surrogate markers for evaluating the process of lung destruction.
  • Evaluation of the use of high-resolution computerized tomography as a diagnostic tool in lung disease.
  • Evaluation of current dosing schedules of AAT augmentation.
  • The formulation of recommendations to speed the development of aerosol AAT for augmentation therapy.

Workshop: Pulmonary Immunobiology and Inflammation.
Outcomes: The workshop recommended the following directions for future research in pulmonary fibrosis:

  • Characterize the mechanisms regulating lung innate immunity and immune tolerance, and the interactions between lung immunity and inflamation. Little is known about how the lung determines whether upregulation of inflammation and an immune response are appropriate for the foreign material that has entered the lung and the role of specific inflammatory and immune cells and mediators in regulating pulmonary inflammation and providing effective pathways to control its overexpression.
  • Define the unique functions of dendritic cells in the lung and how antigens are actively processed in the lung.
  • Determine the mechanism responsible for unique neutrophil and lymphocyte trafficking in the lung and its compartments and how pulmonary lymphocyte trafficking is controlled in both primary and memory immune responses.
  • Define host pathogen interactions that lead to persistent lung damage and mechanisms of inflammation-induced structural damage to the lung.
  • Determine how environmental factors, prior lung injury, or previous pulmonary immune responses interact with genetically determined immune responsiveness to affect subsequent lung inflammatory and immune responses.

Symposium: Lamposium 2000
Cosponsor: The LAM Foundation, a private patient advocacy organization that raises funds for LAM research and provides research grants. In addition, the organization promotes NHLBI and other LAM research activities, provides information about LAM to LAM patients and their families, and will serve as a major source of patient referrals to the NHLBI Registry.

Symposium: The International LAM Symposium Cosponsor: The LAM Foundation and Columbia University

Meeting: Primary Pulmonary Hypertension Grantee Meeting, Cosponsor: ORD Purpose: Bring together PPH investigators funded by NHLBI to review current research developments, increase communication between investigators regarding patient care and treatment, and develop a framework for future research in vascular biology and PPH. Outcomes: Recommended areas for future research emphasis include the following:

  • Make a concerted effort to identify the gene for familial PPH and understand its biological significance.
  • Emphasize a better understanding of the basic biological mechanisms of vascular remodeling and vascular constriction occurring with PPH and better integration of research results from different laboratories.
  • Make better use of familial data and samples that have been collected over the years in studies analyzing specific mediators of the disease.
  • Define more effective and better treatment alternatives and identify and evaluate novel therapies that include combination therapies.

Sickle Cell Disease Program Workshops, Symposia, and Meetings

  • Comprehensive Centers Directors Meeting.
  • Scientific Abstracts Presentation.
  • Nutrition in Hemoglobinopathies Workshop.
  • Polymorphonuclear Cells in Sickle Cell Disease Workshop.
  • CSSCD Steering Committee Meeting.
  • MSH Patients' Followup Steering Committee Meeting.
  • STOP Trial Steering Committee Meeting.
  • PED HUG Steering Committee Meeting.

    Meetings: Discussions began in 1999 regarding establishment of a mechanism to cofund clinical research in marrow transplantation. The discussants included NHLBI, NCI, the International Bone Marrow Transplant Registry, the National Marrow Donor Program, and the American Society for Blood and Marrow Transplantation. Communitywide meetings were held in Keystone, CO, and Anaheim, CA. The concept of a marrow transplant network received enthusiastic support.

Problem Areas Related to Rare Diseases

alpha symbol1-Antitrypsin Deficiency

A shortage of product exists for the treatment of patients with AAT deficiency. Only one product has been approved by the FDA. Its approval was based on increasing the level of AAT in the blood without evidence of clinical benefit. New products are in various phases of evaluation, and much debate focuses on whether a clinical trial is needed to assess the clinical efficacy of these new products before they are approved.

Arrhythmogenic Right Ventricular Dysplasias

The major problems with ARVD are in developing effective means for its diagnosis and treatment. ARVD is extremely rare and often goes unrecognized, so it has only recently been shown to have a genetic association. An international collaboration of scientists working in this area has recently been organized and should facilitate pathological, molecular, and genetics research on its pathogenesis.

Bronchopulmonary Dysplasia

Lack of information about lung development remains a barrier to the development of therapies for BPD. In addition, current knowledge about BPD is sometimes not applied in the clinical setting.

Brugada Syndrome

The diagnosis of Brugada syndrome is difficult to confirm based on detection of specific mutations in the sodium channel gene thought to underlie its development. No preventative therapies are available. The only means of preventing premature death lies in the use of an implantable cardiac defibrillator capable of detecting bradyarrhythmias.

Congenital Heart Block in Neonatal Lupus Syndromes

Until the recent development of an appropriate animal model for CHB in neonatal lupus syndromes, research in the area has been dependent on the use of human fetal tissue, a procedure now banned under PHS guidelines.

Creutzfeldt-Jakob Disease

No clear and unequivocal clinical criteria exist for reliable diagnosis of CJD. Laboratory diagnosis is currently based exclusively on histopathological findings in brain biopsy/necropsy. The lack of a reliable presymptomatic test for this transmissible disease is the major impediment for progress in the prevention and treatment of CJD.

Fanconi Anemia

The identification of eight distinct complementation groups represents a high degree of locus heterogeneity, which complicates the molecular diagnosis of FA and may make screening cumbersome. However, certain complementation groups prevail in specific populations (FA-C in Ashkenazi Jews; FA-A in SA Afrikaans-speaking people and Italians), which helps to set priorities for mutation screens. The FA-A and FA-C proteins have no sequence homologs in the current databases, although structural homologs may exist. Thus, resolution of difficulties in FA protein purification and the pursuit of the X-ray crystallographic structure of these proteins is considered a high priority. The function of these proteins, the nature of their interaction with other proteins in the Fanconi protein complex, and the relation of these complexes to DNA repair remain to be determined.

Graft Versus Host Disease

The nature of the responding cells in GVHD and reliable methods to predict and ameliorate the problem remain elusive. A challenge remains in fostering graft versus leukemia or graft versus tumor while avoiding GVHD. In addition, the basic immunology, biology, and tissue specificities of the response require further definition.


Scarcity of data and LAM tissue has hindered learning about the etiology and pathogenesis of LAM. The small number of patients makes it difficult to learn about important aspects of the disease, such as its prevalence, prognosis, and clinical course and the effect of various treatments. A lack of animal models makes it necessary to obtain human cells or tissue to do LAM research. The registry will facilitate collection of clinical data and tissue and will identify a cohort of LAM patients who might be contacted in the future, if opportunities for clinical studies arise. The LAM Foundation continues to facilitate collection of LAM tissue at the time of lung transplantation. Progress in LAM research has increased the demand for this scarce resource. An NHLBI LAM Tissue Committee is establishing procedures and guidelines for LAM tissue collection and distribution of LAM tissue.

Long QT Syndrome

A critical issue with LQTS is the need to rapidly screen potential gene carriers to confirm physician diagnosis. Improvements in therapy are also urgently required. Implantation of cardiodefibrillators is a costly approach designed to effect rescue from sudden death by employing an electrical shock to the hearts of victims once they have collapsed. Better means of preventing dangerous arrhythmias in LQTS patients are necessary possibly via drugs targeted to the specific type of gene mutations in each carrier. Available drug therapies may be appropriate for some affected individuals but contraindicated for others. Because the disease may not be recognized simply on the basis of ECG abnormalities, improved means of recognizing its electrical signature would also be valuable, especially for children, as soon as the disease becomes apparent.

Investigators are working to increase the visibility of the LQTS registry with African Americans. Whether LQTS is less common among them or whether African Americans are referred to the registry with less frequency compared with the white population remains unknown.

Primary Pulmonary Hypertension

No animal models completely mimic PPH in humans. The etiology and pathogenesis of PPH must be understood before successful therapies can be developed. Current therapies are cumbersome, expensive, and not effective for all patients. Despite the rarity of PPH, several basic research scientists and clinical investigators continue to devote their careers to defining the cellular and molecular mechanisms of PPH and to improving therapeutic modalities for affected patients.

Pulmonary Alveolar Proteinosis

More basic research is needed on the etiology and pathogenesis of PAP. Advances in gene therapy will affect therapies for PAP.


The NHLBI clinical trial for pentoxifylline for sarcoidosis has had problems in recruiting patients. To address this, they have initiated vigorous outreach, including collaboration with the Pulmonary Medicine Department at Howard University, a regional sarcoidosis center.


Several challenging problem areas are associated with thalassemia. The characteristic facial and bodily deformities associated with the disease are more troublesome to patients as lifespan for these individuals increases into the third and fourth decades. In addition, several comorbidities associated with chronic transfusion therapy remain troublesome, including infectious diseases such as HIV and hepatitis C, and iron overload still occurs despite available chelation therapy. The problem of cardiac morbidity and mortality in thalassemia patients requires further study. Finally, several areas in the chemistry and physiology of iron remain unresolved, including the nature of iron toxicities and their tissue specificities, new approaches to chelation, the burden of parenteral desferal therapy that is often omitted by patients, and the imprecise measures available for body iron burden.

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Last Reviewed: November 4, 2005
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