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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Center for Research Resources (NCRR)

Overview of NCRR Rare Diseases in Children Research Activities, FY 2000–FY 2005

NCRR develops and supports critical research technologies that underpin health-related research to maintain and improve the health of our nation's citizens. NCRR supports shared resources, sophisticated instrumentation and technology, animal models for study of human disease, clinical research, and research capacity building for under-represented groups. Its mission is achieved through support of a series of grant mechanisms, including large infrastructure grants supporting animal resources, biotechnology, minority research programs, and clinical research. The term of these awards is usually three to five years. The way NCRR centers are configured, the entire Center is funded for a given time, but each individual subproject has a time table of its own (determined by the local governing body) that may even span grant cycles. Consequently, it is difficult to determine the duration of a given project hosted at our NCRR-supported sites.

Through its support of multidisciplinary research, NCRR is uniquely positioned either to provide primary research support or to provide resource support in partnership with other Institutes or Centers to address emerging clinical and basic research needs, such as the study of rare diseases in children. Expansion of NCRR's present efforts in new biotechnologies and instrumentation, development of animal models, and clinical research will foster interdisciplinary collaborations and advance NIH's efforts to study rare diseases of children.

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

Animal Models

Kallmann's Syndrome

Kallmann's syndrome is a neurogenetic disease that affects an estimated 1 in 10,000 males. Patients with this disease suffer from anosmia (inability to smell) and retarded sexual development. These conditions arise because both olfactory nerve axons (and the luteinizing hormone-releasing hormone [LHRH] neurons that migrate with them) fail to make contact with the brain. Loss-of-function mutations in a gene located on the X (female) chromosome KAL1 cause Kallmann's syndrome.

No useful mouse model for this disease is available. A monkey model is currently being developed by NCRR-supported investigators at the University of Nebraska Medical Center in collaboration with the Oregon Regional Primate Research Center. The researchers have obtained the sequence of the complete coding region of the monkey KAL1 gene. Monkey KAL1 protein is 97.4% similar to human KAL1, and analysis of KAL1 expression in the developing rhesus macaque brain is under way. The researchers propose to obtain the basic information and to establish the necessary methodology to develop a functional model of Kallmann's syndrome in the rhesus macaque. The production of such animals would provide: 1) proof that this methodology could be used for the development of primate models of human diseases, 2) the first in vivo model of Kallmann's syndrome, and 3) a primate model to study the role of LHRH neurons in reproductive function.

Niemann-Pick Disease Type C (NPC)

A storage disorder, NPC is characterized by abnormal accumulation of fatty substances in small bodies within the cells known as lysosomes. This human disease presents with a variety of clinical features, including enlarged organs, jaundice, seizures, delayed mental and motor development, and premature death. Onset of NPC can occur over a wide age spectrum, resulting in its classification as infantile, juvenile, or adult (although the adult form is quite rare). Progression is usually slower in patients with later onset. In the United States, approximately 1,000 children are affected. The primary defect is associated with processing intracellular cholesterol. NCRR-supported investigators at Colorado State University have identified and characterized the gene responsible for the most common type of human NPC (NPC1) and a corresponding gene in cats. The researchers have further demonstrated that these genes are similar in 91% of their components. These findings will enable the investigators to characterize the cat NPC model on a molecular, biological, and physiological level and to evaluate various treatment modalities for this human disease. The most promising avenue of further research will be an evaluation of the efficacy of a ganglioside synthesis inhibitor as potential NPC therapy.

Biomedical Engineering and Instrumentation

Sickle Cell Anemia (SCA)

SCA is the most common inherited blood disorder in the United States, affecting about 72,000 predominantly African American (1 in 500) individuals in this country. SCA is characterized by episodes of pain, chronic anemia, and severe infections, usually beginning in early childhood. SCA is caused by an error in the gene that tells the body how to make hemoglobin (the oxygen-carrying component of the blood). This mutation results in the production of structurally abnormal hemoglobin chains, which instead of remaining separate in the cell, clump together into large, inflexible complexes. This abnormal aggregation deforms the red blood cells into curved ("sickle") shapes, causing them to block and rupture tiny blood vessels, depriving organs and tissues of oxygen and causing severe damage.

NCRR-supported investigators at the Rockefeller University have developed a method for producing structurally authentic recombinant hemoglobin molecules in yeast to assist in the study of interactions between hemoglobin chains. The use of recombinant hemoglobin has provided the ability to ask very specific questions about how changes in protein sequence affect protein interactions. The yeast system produces a recombinant sickle hemoglobin that is identical by approximately a dozen biochemical and physiological criteria with the natural sickle hemoglobin purified from the red cells of sickle cell anemia patients. More important, the gelling concentration of this recombinant sickle hemoglobin is the same as that of the sickle hemoglobin purified from human sickle red cells. Fundamental studies are being conducted into the interactions of normal and fetal hemoglobin in order to better understand the correlation between amino acid sequence changes and hemoglobin function. Results obtained thus far show that this system will be very helpful in defining the interactions in normal and sickle hemoglobin chains. This new model system will allow significantly more complex studies of protein interactions in normal and sickle hemoglobin. The more sophisticated understanding of basic biophysical processes at work in SCA may lead to more effective treatments.

Osteogenesis Imperfecta (OI)

OI is a disease that is caused by mutation in the alpha-1 or alpha-2 genes of type I collagen, a structural protein important in bone formation. Mutations can occur in many different positions, and there is currently no known correlation between position of mutation and severity of the disease. An understanding of the nature of the factors that promote stability in the collagen triple helix will give insight into the pathology of the disease. Mutations in the collagen protein chain change its structure and therefore its interaction with other chains to form these important larger structures. NCRR-supported investigators at the University of California at San Francisco have developed computer modeling that has contributed to an understanding of how normal collagen molecules interact to form larger, more stable structures in order to determine the factors that contribute to a loss of stability in that interaction when mutations occur. Molecular dynamics simulations of collagen-like peptides show average structures and internal coordinates similar to x-ray crystallographic structures. These results demonstrate that molecular dynamics can be used to reproduce the experimental structures of fibril proteins by adaptation of software originally designed to model more conventional globular proteins. New information on protein interactions and structure have been reported.

Although fundamental in nature and in its infancy, this work extends the use of computational techniques to the realm of fibril proteins and has provided insight into the way collagen chains interact. Ultimately, an understanding of what factors are responsible for variations in the severity of OI may lead to effective treatments.

Clinical Research Applications

Peroxisomal Disorders

NCRR-supported investigators at the Johns Hopkins University have described an assay useful in testing for the presence of very long chain fatty acids, a blood abnormality observed in the so-called peroxisomal disorders such as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum syndrome. These investigators extended the test to amniocytes and the outermost cells of the membrane surrounding the fetus, thus providing a prenatal test to predict the likelihood of the fetus being affected by these diseases. The investigators report results of 255 prenatal assays identifying 63 affected males. Five families elected to continue the pregnancies, and the abnormality has been confirmed in all these offspring. Among the fetuses that were aborted, the diagnosis was confirmed on autopsy in all. Among those determined by the assay to be unaffected, Zellweger syndrome has been ruled out in all. After 10 years of follow-up, no case of adrenoleukodystrophy has been manifested. Due to the heterogenous presentation of adrenoleukodystrophy, however, these findings are promising but not definitive. Thus, a sensitive and discriminating assay appears to be available for prenatal diagnosis of these serious rare diseases of childhood.

Cystic Fibrosis (CF)

CF is an inherited disease affecting transport of secretions. Thick lung secretions make children with CF particularly vulnerable to lung infections. Pseudomonas aeruginosa infections are particularly problematic in this population. NCRR-supported investigators at the University of Washington reported the results of two multicenter, double-blind, placebo-controlled trials of intermittent administration of tobramycin (an inhaled antibiotic). A total of 520 patients with CF and pulmonary infection with P. aeruginosa infection were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for 4 weeks, followed by 4 weeks with no study drug. Patients received treatment or placebo in 3 off-on cycles for a total of 24 weeks. The patients treated with inhaled tobramycin experienced improved lung function (a 10% increase in FEV1, a measure of airway compliance), while patients receiving placebo had a statistically significant 2% decline in this measure. In the tobramycin group, the density of Pseudomonas in the sputum decreased by an average of 0.8 log colony-forming units, compared with an increase of 0.3 log units in the placebo group. These differences were statistically significant. The patients in the tobramycin group were 26% less likely to be hospitalized for antibiotic treatment of Pseudomonas infection than those in the placebo group. Inhaled tobramycin was not associated with detectable toxicity of the ear or kidney or with accumulation of the drug in serum. In summary, inhaled tobramycin was well-tolerated, had no serious side effects, and improved pulmonary function, decreased the density of Pseudomonas in sputum, and decreased the risk of hospitalization.

Severe Combined Immunodeficiency (SCID)

NCRR-supported investigators at Duke University summarized their experience with 89 consecutive patients treated for inborn errors of the immune system classified as SCID. Patients were treated with bone marrow transplantations and were surveyed between 3 months to 16.5 years post-transplantation. Of particular interest were the relative outcomes of patients receiving genetically matched (HLA-identical) versus genetically half-matched (HLA-haploidentical) donations of marrow. While some patients have a sibling with the identical histocompatibility genes, others do not and must rely on a donation from a parent, who is only half- or haploidentical. The exactness of the match is important because although the patient (having no immune system) cannot reject the donated marrow, the marrow, once reconstituting the immune system, can recognize the recipient's body as foreign and cause a serious condition known as graft versus-host disease (GvHD).

The hope is to maximize the chance for rebuilding the immune system while minimizing the chance of rejection. It was theorized that if the donor bone marrow was first depleted of T cells (those cells associated with GvHD) before transplantation, that both conditions would be satisfied. In reviewing the data, these investigators reported an overall 81% survival rate. Those 12 having had transplantations with immunologically identical donors were all alive. Sixty of 77 (78%) of those who received half-identical donations were alive. The latter group included two of three who, in addition to the bone marrow, received placental blood as a source of stem cells. Other factors favoring survival were gender, ethnicity, and age at transplant. All the transplanted girls survived, whites had a better survival than blacks or Hispanics, and 95% versus 76% of children transplanted before the age of 3.5 months survived. There were no deaths attributed to GvHD, although one recipient (of a half-matched donation plus placental blood) is being treated with continuous cyclosporine for chronic GvHD.

Future Plans for Research Activities

NCRR does not plan to issue any specific requests for applications, requests for proposals, program announcements, or workshops in the area of rare diseases in children during FY 2001- FY 2005. Through its support of unique resources, NCRR contributes a significant portion of its budget to rare diseases in general and to rare disease in children in particular. The demand for NCRR-supported resources determines scientific and funding shifts. Therefore, future increases in rare diseases research in children supported by other components of NIH will result in corresponding NCRR increases.

Of note is that NCRR cosponsors a network of National Gene Vector Laboratories. These facilities are composed of an interactive group of academic laboratories functioning through a cooperative agreement and charged with providing vectors for clinical trials to eligible investigators in the gene therapy field. Through a request for applications in FY 2001, NCRR and its co-sponsors are seeking submission of competing grant applications for this resource, which has been and will continue to be instrumental in advancing the study of genetic diseases, including rare diseases in children. Successful applicants may be approved for funding through FY 2006.

 


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Last Reviewed: February 1, 2005
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