Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Center for Research Resources (NCRR)


The National Center for Research Resources (NCRR) develops and supports critical research technologies and resources that facilitate biomedical research to improve the health of citizens of the United States. NCRR supports shared resources, sophisticated instrumentation and technology, animal models for the study of human disease, clinical research resources, and research capacity building for underrepresented groups.

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

Science Advances

Ataxia-telangiectasia (AT) is a rare, inherited disorder associated with the inability to coordinate muscle movements, nystagmus, slurred speech, involuntary muscle jerks, decreased reflexes, and, occasionally, sensory defects. In addition, patients with AT have immune deficiencies leading to recurrent pulmonary infections, leukemia, and cancer. They also have an increased incidence of diabetes. Disease severity is highly variable, with some patients wheelchair bound and dying in childhood and others living to middle age. The AT gene encodes a protein with similarities to proteins involved in cellular signal transduction and control of the cell cycle. Through the NCRR Institutional Development Award (IDeA) Program researchers at the University of South Dakota have shown that the AT gene may be responsible for several errors in the biochemical signaling pathways that regulate not only blood sugar levels but also cell growth and cell division. Understanding the failures in signaling associated with the AT gene may lead to new approaches to treating this disease and offer new insights into the fundamental biochemistry of cell growth and cell division needed to understand a number of other diseases such as cancer and diabetes.

Chromosome 18q deletion syndrome is a genetic disorder caused by deletion of the terminal part of the long arm of chromosome 18, resulting in multiple congenital malformations. The phenotype is highly variable but is characterized by mental retardation, short stature, hypotonia, hearing impairment, and foot deformities. Deletion syndromes of chromosome 18p- and 18q- are rare; the estimated frequency is about 1/40,000 births (approximately 100 U.S. babies per year). Researchers at the Oklahoma Medical Research Foundation in Oklahoma City are exploiting the advances made in sequencing the human and mouse genome, genetic engineering, and DNA manipulation to model the human 18q- syndrome in the mouse. Study of this mouse model should greatly accelerate insight into the pathogenesis of this syndrome at the molecular level. Knowledge gained from the model will lead to novel strategies for diagnosis and treatment of this syndrome.

Lysosomal storage disorders are a group of more than 30 inherited disorders resulting from the body’s inability to produce certain enzymes necessary to break down and recycle large molecules. The lack of enzyme activity results in the accumulation (storage) of large molecules, which results in cell damage that can be apparent at birth or develops with aging. The diseases can affect multiple organ systems, often including the brain, resulting in mental retardation and a short life span. In the United States, these disorders are estimated to affect 1 in 7,000 births. An NCRR-supported research team at the University of Pennsylvania School of Veterinary Medicine has discovered cats and dogs with several of these diseases, including mucopolysaccharidosis (MPS) types I, IIIB, VI, and VII; alpha-mannosidosis; Krabbe disease; and mucolipidosis II. These animals have assisted in the ongoing evaluation of therapies, including enzyme replacement, bone marrow transplantation, and gene therapy using retrovirus and adeno-associated virus vectors. Gene therapy studies have been successful in preventing many of the clinical manifestations of lysosomal storage disease in these animals. These studies in large animal models are promising for the future use of gene therapy in clinical trials in humans.

Periventricular leukomalacia (PVL) is the principal form of perinatal brain injury and leads to cognitive and motor performance defects. The cause and mechanism of defects in PVL are not well understood. The NCRR-supported Neuroimage Analysis Center at Brigham and Women's Hospital in Boston applied its imaging tools to the study of PVL. This study used magnetic resonance imaging (MRI) and the Center's analysis tools to quantitatively assess the damage associated with this disease in different structures in the brain, including the cortex, basal ganglia, cerebellum, and white matter fiber tracts. The study has provided insight into potential causative factors of this poorly understood disease. It has also established an important quantitative baseline against which future treatments of the disease can be assessed.

Retinal degeneration is seen in several rare diseases associated with neural degeneration. Under the auspices of an NCRR-supported K23 career development award, patterns of gene expression and specific protein synthesis in normal mice and in a mutant mouse strain that exhibits retinal degeneration as a result of apoptosis of photoreceptors were compared. The researchers identified a panel of signaling and apoptosis-associated molecules previously not known to be involved in photoreceptor degeneration. Several of these proteins occupy central positions in known signaling pathways not previously associated with retinal degeneration.

In addition, using a mouse model system, NCRR-supported researchers at the University of Oklahoma Health Sciences Center are investigating the molecular and cellular basis for the observed loss of retinal photoreceptor cells when two defective copies of a particular photoreceptor gene are inherited. Recently, they showed that direct injections of certain growth factors delay retinal degeneration in these mice by turning on conserved cellular signaling pathways that promote cell survival. Further studies to understand the mechanism of protection may lead to new therapies that prevent or slow the onset of blindness in affected persons.

Significant Ongoing Rare Diseases Research Initiatives

Rare Diseases Clinical Research Network

The Rare Diseases Clinical Research Network (RDCRN), a collaboration between NCRR and the NIH Office of Rare Diseases with support from several other NIH Institutes, has grown with the addition of three new Clinical Research Consortia. Thus, the RDCRN currently consists of 10 Rare Diseases Clinical Research Consortia (RDCRC) and the Data and Technology Coordinating Center (DTCC). This past year, while each RDCRC focused on development of clinical protocols for a subset of related rare diseases, the DTCC developed and enabled technology, tools, and services for the network, including electronic data entry, remote direct laboratory transfer, vocabulary and laboratory standards, statistical support, Web site development and maintenance, and database querying tools. The RDCRN vocabulary unit has been instrumental in incorporating standards across networks and development of an adverse event reporting system. In addition, in collaboration with national standards organizations, including the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT), Health Level Seven, and the National Library of Medicine, the DTCC has facilitated the incorporation of unique concepts and terms necessary for rare diseases in national vocabularies.

The patient support groups affiliated with each of the consortia have formed the RDCRN Coalition of Patient Advocacy Groups (CPAG) to work together to support each other in their outreach efforts to patients afflicted with rare diseases, their families, and the public. One of their first projects is to develop information on the diseases targeted in the RDCRN for emergency room physicians, who may be seeing an individual with a rare disease for the first time. The DTCC, in collaboration with each RDCRC, has implemented a patient contact registry, which allows individuals with each of the targeted rare diseases to register to receive information about new or ongoing clinical studies or trials in the Consortia in addition to periodic educational updates from the network. While no studies began in the first year, many Consortia have been busy with the development of longitudinal studies as well as clinical trials of potential new therapeutic agents. Most Consortia have begun training programs focused on the creation of a cadre of clinical investigators interested in rare diseases. The RDCRN Web site ( is a source of information for the public, physicians, patients, and investigators about rare diseases. The patient contact registry is Web enabled and accessible from the Web site.

Industry-initiated Rare Disease Research Supported at General Clinical Research Centers (GCRCs)

The NCRR-supported GCRCs host much of the research focused on rare diseases, as there are few large clinics available specifically for these unusual disorders. While most of these studies are investigator initiated, there are industry-sponsored phase 1, 2, and 3 trials of new interventions that utilize the GCRCs. Since the number of affected individuals is small, the expected market is also small, limiting the interests of many pharmaceutical companies. Recognizing the need to advance the development of new agents for these diseases, the Orphan Drug Act provides incentives for companies to develop and license agents for rare diseases. The NCRR, also recognizing the need and benefit from support of new agents for rare disease, modified the guidelines for GCRCs for industry-initiated studies and trials. Normally, companies that wish to utilize the resources of the GCRCs in the performance of their studies must pay for those resources. For industry-supported rare disease studies and trials, the GCRC may approve use of GCRC resources without charge. Several rare disease studies are already benefiting from this change, including cystic fibrosis, lysosomal storage diseases, and urea cycle disorders.

Activities with Nonprofit Organizations

In partnership with the Cystic Fibrosis Foundation (CFF), NCRR supports a novel approach to develop new therapeutics for cystic fibrosis, a rare genetic disease. The CFF Therapeutics Development Network (TDN) unites investigators focused on cystic fibrosis research to perform clinical trials of promising agents for treatment and cure of this disorder. NCRR-supported GCRCs, which provide personnel, resources, and space for the conduct of clinical research, are utilized by many investigators in this network. In addition, NCRR supports a coordinating center, which provides informatics support for the management, conduct, and analysis of the studies. This bioinformatics component includes a secure, interactive Web environment for network communication and data entry as well as a biostatistical unit. These resources facilitate transfer of new discoveries from bench to bedside.

The National Disease Research Interchange (NDRI) is a not-for-profit organization in Philadelphia, founded in 1980. NCRR provides support for approximately one-third of their activities via a cooperative agreement. NDRI personnel obtain commitments from academic pathologists to provide human tissues for basic research and statements of need according to specific protocols from biomedical researchers. These two lists, with very specific clinical details (but without patient identifiers), are kept in NDRI databases. When a tissue becomes available, a researcher is contacted by NDRI staff and asked if he/she can accept it. Upon positive reply, the pathologist is notified; prepares the tissue according to the researcher’s protocol; and sends it, anonymized, to the researcher. The researcher pays a relatively small fee. Through this cooperative agreement, NDRI facilitates laboratory research on a broad variety of rare and common diseases. The agreement is currently co-funded by NCRR, the Office of Rare Diseases, and four other NIH Institutes and Centers.

Rare Disease-specific Conferences, Symposia, or Meetings

In collaboration with the Office of Rare Diseases, NIH, NCRR organized a meeting of the representatives of the patient advocacy groups that are associated with the Rare Diseases Clinical Research Network on July 28 – 29, 2004. This meeting provided an opportunity for all of the lay groups working with the Rare Diseases Clinical Research Consortia to share experiences and explore ways that their efforts could be synergized. The morning session provided an overview of how NIH works, the “Common Rule” from the Office of Human Research Protections, and the Health Insurance Portability and Accountability Act (HIPAA) from the NIH Office of the Director. The afternoon was composed of four panels, each with three representatives from member advocacy groups. These sessions discussed Recruitment, Web Resources, Dissemination of Study Results to Patient and Physician Communities, and Mechanisms for Working Together across Diseases. As a result of this meeting, the RDCRN CPAG was formed. All present were very excited about the sharing that went on at the meeting and working together on shared goals. Co-leaders of the CPAG were elected and two subcommittees were organized. One subcommittee will work to develop, in collaboration with their Consortia, information for emergency room physicians who may be encountering a patient with a rare disease for the first time. The other subcommittee will work to develop best practices, resources, and practical guidelines for obtaining Continuing Medical Education credits for physicians and nurses for rare disease meetings. The two large umbrella organizations for rare diseases, NORD and the Genetic Alliance, actively participated and are part of the new CPAG.


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Last Reviewed: July 22, 2005