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

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

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

The mission of NIAMS is to support basic and clinical research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of scientists to carry out this research, and the dissemination of information on research results in these diseases. Some of these diseases are rare and occur in children. Included in this group are rheumatic conditions such as juvenile rheumatoid arthritis and familial fever syndromes, muscle diseases such as Duchenne's muscular dystrophy and facioscapulohumeral dystrophy, musculoskeletal disorders such as osteogenesis imperfecta, and skin diseases such as epidermolysis bullosa, ichthyosis, and pseudoxanthoma elasticum. NIAMS-sponsored research has advanced understanding of these diseases, and several initiatives are under way. Other initiatives are being planned.

Recent Scientific Advances in Rare Diseases in Children Research

The conditions discussed below are under investigation by more than one investigator with support from NIAMS. All of these projects were funded in FY 2000. These conditions are in areas within the mission of NIAMS, and the Institute will be interested in funding future research in these areas.

Juvenile Rheumatoid Arthritis (JRA)

Etanercept has been shown to be a safe and effective drug in the treatment of children and teenagers with JRA, a type of arthritis that causes joint inflammation and stiffness for more than 6 weeks and begins when the child is 16 years of age or younger. In a clinical trial coordinated by the NIAMS Multipurpose Arthritis and Musculoskeletal Diseases Center at the Children's Hospital Medical Center of Cincinnati, investigators in the Pediatric Rheumatology Collaborative Study Group injected 69 children with etanercept twice a week. At the end of three months, all measures of arthritis impact (symptoms, joint abnormalities, ability to perform daily functions, and laboratory tests) were dramatically improved. Furthermore, the drug was well-tolerated.

The success of this clinical trial marks the culmination of many years of basic research supported by NIAMS and other NIH components. Etanercept belongs to a new class of drug treatments called biologic agents, which are designed to interfere with the specific biological process of a disease. The drug acts as a sponge to absorb a tumor necrosis factor, which is a naturally occurring protein that causes inflammation.

Duchenne's Muscular Dystrophy (DMD)

DMD is a genetic muscle-wasting disease caused by mutations in the gene for the protein dystrophin. NIAMS-funded scientists recently reported a number of exciting advances in mouse models of DMD. These include the successful application of the common antibiotic gentamicin to restore the function of the dystrophin protein, and the successful use of gene replacement to restore the missing protein and thereby reduce muscle disease. Such animal studies hold promise for potential future therapies for human patients affected by DMD.

Osteoporosis and Children

Osteoporosis, a bone-thinning disease that can lead to fractures, may actually start in childhood. Research studies on young girls have revealed that minor variations in a gene for the bone protein collagen can lead to lower bone density. In one investigation, more than 100 prepubertal girls were measured for bone mineral density. Also assessed were the bone size and genetic makeup of the collagen gene in each girl. The researchers found that girls with a particular type of collagen gene variant had almost 50% lower bone mineral density than girls with a different collagen gene variant. Identifying and understanding genetic susceptibility to osteoporosis early in life may facilitate the targeting of interventions to those who will most profit from them.

Pseudoxanthoma Elasticum (PXE)

PXE is an inherited disorder characterized by progressive calcification of elastic fibers in the skin, eye, and cardiovascular system. Scientists studying PXE have identified the gene that causes this disease. The researchers took a population genetics approach to narrow the location of the gene to a portion of human chromosome 16, and one gene in this region (MRP6) was later determined to be the gene associated with the disease. Work is continuing to determine the function of the gene and how mutations in it result in clinical disease. This could lead to the design of therapeutic interventions to treat PXE.

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

This Institute's report notes several RFAs issued in 2001. The results and advances these RFAs may produce is yet to be determined. At this point, NIAMS has no commitments for FY 2002 - FY 2005 on rare diseases and conditions in children.

Opening of NIH Pediatric Rheumatology Clinic

The NIAMS Intramural Research Program launched an initiative in the fall of 2000 at the NIH research hospital, the new NIH Pediatric Rheumatology Clinic. The Clinic offers diagnosis, evaluation, and treatments for children with rheumatic diseases. In addition to JRA and familial fever syndromes, pediatric rheumatic diseases include lupus, scleroderma, and dermatomyositis. The Clinic is providing children with a place where they can be diagnosed and treated in a state-of-the-art facility, and researchers can learn more about rare rheumatic diseases in children.

In February 2001, NIAMS convened a roundtable meeting to consider current and future research needs and opportunities in pediatric rheumatology. NIAMS staff will be developing initiatives based on the recommendations of the medical experts who attended the meeting.

New Research Centers for Juvenile Rheumatic Diseases

In FY 2001, a Rheumatic Diseases Core Center was established at the Children's Hospital Medical Center in Cincinnati. The Center will concentrate on understanding the causes of and finding novel approaches to treating pediatric rheumatic diseases. The Center will comprise five cores:

  • A repository to make tissues available to researchers.

  • Magnetic resonance imaging (MRI) to monitor disease progression.

  • Identification of cells involved in rheumatic diseases.

  • Data processing and bioinformatics.

  • Administrative support to coordinate projects.

Two pilot studies will be undertaken by the Center. The first will examine the relationship between a protein produced in response to inflammation and activation of the inner cells of blood vessels in the synovium (a lubricating tissue surrounding movable joints) of children with JRA. The second will study the effect of certain enzyme inhibitors on the production of antibodies against a child's own tissues in lupus nephritis, a kidney disease.

The Children's Hospital in Cincinnati is also the site of a Multidisciplinary Clinical Research Center, which was established in FY 2001. Projects to be conducted by this new Center include research on childhood-onset dermatomyositis (a rare, sometimes fatal disease in which the muscles and skin become inflamed), juvenile fibromyalgia (a chronic disorder characterized by widespread musculoskeletal pain and fatigue), quantitative MRI to assess JRA, and the relationship between genetic factors and responses to drugs.

Osteogenesis Imperfecta (OI)

NIAMS has a long-standing interest in OI, a genetic disorder characterized by bones that break easily, often for little or no apparent cause. NIAMS recently funded five new grants in OI supporting research activities ranging from cutting-edge gene and cell therapies to testing drug treatments in mouse models. Furthermore, along with several other Institutes, NIAMS is sponsoring an RFA entitled, "New Research Strategies in OI," which was issued in December 2000. NIAMS is also participating in an RFA on "Clinical Trial Planning Grants for Pediatric Rehabilitation." This RFA was issued in November 2000 and focuses on pediatric musculoskeletal conditions, burn wounds, and genetic skin disorders.

Hereditary Multiple Exostoses

Hereditary multiple exostoses is a skeletal disorder that primarily affects bone growth in children. Patients with this disease present with benign cartilage-capped exostoses (growths projected outward from the surface of a bone), usually originating in the growth plate, and typically have short stature and curved bones. A significant proportion of the patients will develop malignant chondrosarcoma, a cancer originating from cartilage cells. Even in the absence of malignancy, the disease can be debilitating when the exostoses compress soft tissues such as surrounding muscles or nerves. The only known treatment is surgical removal of the exostoses, which often grow back at the original site. NIAMS is planning to support a two-day meeting on multiple hereditary exostoses at the University of Arizona in Tucson in November 2001.

Duchenne's Muscular Dystrophy (DMD)

In May 2000, NIAMS partnered with the National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Diseases (ORD) to sponsor a scientific workshop on Therapeutic Approaches for DMD. The meeting provided an opportunity for DMD investigators to share new findings, identify gaps in current research, and recommend future directions for promising studies of this disease. The insights from this conference are being used to develop new NIH research solicitations in DMD and other muscular dystrophies. These initiatives will build on projects funded through the currently active FY 1999 program announcement on "Pathogenesis and Therapy of the Muscular Dystrophies."

Facioscapulohumeral Muscular Dystrophy (FSHD)

NIAMS has a number of initiatives under way in the area of FSHD, a genetic disease of the skeletal muscle that leads to progressive weakening of the muscles of the face, shoulders, and upper arms. Several projects with potential implications for FSHD have been funded as a result of the above-mentioned FY 1999 Program Announcement (PA) on pathogenesis and therapy, including grants focused on developing safe and effective methods to perform gene therapy on skeletal muscle.

Last spring, together with NINDS, ORD, the FSH Society, Inc., and the Muscular Dystrophy Association of America, NIAMS co-sponsored a scientific conference on the "Cause and Treatment of FSHD." Researchers from the United States, Canada, Europe, South America, and Asia met to share their latest findings and identify directions for future investigations. The recommendations that emerged from the conference include efforts to enhance understanding of the molecular processes and tissue changes associated with FSHD, ways to explore possible therapies to treat the disorder, strategies to promote the establishment of population-based studies of the disease, and development of research resources. Implementation of these recommendations has begun with the issuance of a November 2000 RFA entitled, "Exploratory Research on Facioscapulohumeral Dystrophy."

To develop research resources for FSHD, NIAMS has joined with NINDS to fund a registry on FSHD and another form of muscular dystrophy known as myotonic dystrophy (DM). The long-term goal of the registry is to facilitate research in FSHD and DM by serving as a liaison between families affected by these diseases who are eager to participate in specific research projects and investigators interested in studying these disorders. The registry will recruit and classify patients, and store medical and family history data for individuals with clinically diagnosed FSHD and DM. Scientists will be provided with statistical analyses of the registry data, as well as access to registry members who have agreed to assist with particular research studies.

Muscular Dystrophy (all forms)

To stimulate further research on all forms of muscular dystrophy (inherited disorders in which there is progressive degeneration of muscle fibers), NIAMS issued a program announcement with set-aside funds, "Therapeutic and Pathogenic Approaches for the Muscular Dystrophies," in January 200l. Responses to the announcement may include studies in appropriate animal models or preclinical or clinical studies in patients with DMD, Becker muscular dystrophy, FSHD, limb-girdle muscular dystrophy, DM, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, or other forms of muscular dystrophy.


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Last Reviewed: February 1, 2005
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