Overview of NIAMS Rare Diseases Research Activities
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. NIAMS-supported researchers have made significant progress in broadening the base of knowledge related to many of the rare diseases within the Institute’s scope. Many of our new and ongoing basic and clinical research studies are aimed at reducing the burden associated with disease as well as the development of new treatment options.
Recent Scientific Advances in Rare Diseases Research
Epidermolysis bullosa is a group of hereditary rare blistering diseases of the skin. The disease is a result of defects in the type VII collagen, a molecule involved in anchoring the epidermis to the dermis. There has been much work investigating the use of gene therapy to provide a method to correct the collagen defect in epidermolysis bullosa. To date, while there has been some success in animal models, nothing has progressed to successful human clinical trials using this approach. NIAMS-supported researchers are exploring alternative methods of correcting the defect by providing the gene product, in this case normal human type VII collagen, rather than correcting the defective gene by introducing new genetic material, as with gene therapy. While this method would not allow for the development of the gene product naturally, it would provide a more physiologic method of trying to treat and heal the wounds that develop in patients with this disease. Using both human and mouse skin models, NIAMS-supported researchers injected human recombinant type VII collagen into the part of the skin where it is normally found in both models. Once injected into the right area, the collagen organized into its normal structure in the appropriate location and reversed the features of epidermolysis bullosa in both the human and animal skin models. This research provides a novel alternative to gene therapy for the treatment of the severe forms of this disease.
One of the primary functions of the outermost layer of skin is to act as a barrier both to loss of water and nutrients from within the body and to prevent foreign chemicals from entering the body. This function is accomplished by the outermost layer of skin called the stratum corneum. Ichthyosis is a heredity disease that has barrier function defects because of abnormalities in the stratum corneum. NIAMS-supported researchers have been investigating the molecular basis of the development of the barrier function in order to better understand the defects associated with ichthyosis. These researchers are examining a molecule involved in the production of a form of vitamin D in the skin and its role in the normal maturation of the skin and production of the barrier. To investigate the function of this molecule, researchers created a mouse model in which the gene for this form of vitamin D was removed. In animals with only one rather than two genes for this form of vitamin D the skin looked normal. However, when assessed by a variety of biochemical measures and markers of stratum corneum function, it was noticed that the stratum corneum had decreased quantities of these molecules. When barrier function was tested by measuring water loss, it was found to be normal in the resting state but delayed in recovery following injury. Thus, this form of vitamin D is essential for the normal recovery of a barrier function following injury. Understanding the barrier function and its defects in certain skin diseases will allow for development of novel treatment options for individuals with ichthyosis and other diseases associated with abnormal barrier function.
Juvenile Rheumatoid Arthritis
Juvenile rheumatoid arthritis (JRA) is characterized by inflammation that causes redness, swelling, warmth, and soreness in the joints. Besides joint swelling, systemic JRA is characterized by fever and a light skin rash and may also affect internal organs such as the heart, liver, spleen, and lymph nodes. A genetic variation within the IL-6 gene increases susceptibility to systemic JRA, according to researchers funded by the NIAMS and the Arthritis Research Campaign. Researchers from around the world collaborated to collect DNA samples from children with systemic JRA and one or both parents. The transfer of genetic information from parent to child was analyzed, and the scientists found excess transmission of a genetic variation (-174G nucleotide variant) within the IL-6 gene from parent to child. Children who developed systemic JRA at age 5 or older showed significantly higher levels of this variant compared to the children who developed the disease before age 5. These findings suggest that there may be distinct genetic profiles for the disease that result in differences in age of onset and disease severity. Continuing to uncover disease-associated genes may lead to health care providers having clinically useful subgroupings of systemic JRA.
Muscular dystrophy refers to a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal or voluntary muscles, which control movement and breathing. The muscles of the heart and some other involuntary muscles are also affected in some forms of muscular dystrophy, and a few forms involve other organs as well. NIAMS-supported researchers have discovered and demonstrated in mice a method of delivering genetic therapy for muscular dystrophy and perhaps other diseases of the muscle or heart. Their research shows for the first time a method by which a corrected gene for dystrophin (a protein found in normal muscle tissue) can be delivered systemically to the affected muscles of a mouse with a disease that resembles Duchenne muscular dystrophy. Scientists found that by combining a single injection of an adeno-associated viral (AAV) vector (a viral “vehicle” carrying a mini-dystrophin gene) into the bloodstream, along with a dose of the hormone-like substance vascular endothelial growth factor, they were able to increase the efficiency of delivering the therapeutic virus into the muscle tissue. This treatment resulted in widespread expression of dystrophin in skeletal muscle tissue and improvement in several of the measurements of muscle integrity and function. These findings suggest an approach for overcoming one of the significant obstacles of gene therapy for muscular dystrophy, that of efficient delivery of therapeutic genes in the skeletal muscle cells. The Muscular Dystrophy Association also helped fund this research.
Researchers in the Intramural Research Program at NIAMS are exploring the development of potential treatments that would promote the regeneration of damaged muscle. These treatments, the researchers say, could be based on a protein called follistatin, which they have discovered plays a critical role in the growth and regeneration of adult skeletal muscle cells, and/or a group of chemicals called histone deacetylase (HDAC) inhibitors that help follistatin do its job. Researchers have found that the level of follistatin is significantly elevated in muscle cells when they are treated with HDAC inhibitors. HDAC inhibitors stimulate the formation of mature muscle cells from immature precursor cells. When follistatin levels are reduced, however, HDAC inhibitors no longer stimulate adult muscle growth, the researchers found. The regeneration activities of the HDAC inhibitors appear to function only in skeletal muscle, since follistatin is not stimulated in other cells tested. In animal studies, administering an HDAC inhibitor produced signs of muscle regeneration in regions of injured skeletal muscle tissue. This study establishes for the first time that follistatin promotes the recruitment and fusion of immature muscle cells to pre-existing adult muscle fibers.
Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare, inherited disorder in which bone is fragile and highly vulnerable to fracture. The vast majority of OI cases are due to mutations in a gene that produces type I collagen, a protein that forms a network of fibers in bone and provides much of the tissue’s strength. Although gene therapy is likely to remain experimental for some time, the goal of being able to repair genetic mutations through gene therapy techniques is being explored. The challenge for researchers has been the ability to target the appropriate gene and insert new genetic material at the correct location on the type I collagen gene without affecting other unrelated genes. Using mouse models, NIAMS-supported researchers have been able to successfully insert the genetic material into the collagen gene. Importantly, cells in which the defective collagen gene was inactivated were shown to produce normal collagen and to retain the ability to develop into mature bone-forming cells.
New/Planned Extramural and Intramural Research Initiatives
Juvenile Rheumatoid Arthritis
NIAMS supports a state-of-the-art genomics project to uncover gene expression patterns that contribute to the development of pediatric arthritis. By using DNA microarrays—small silicon chips that contain tiny amounts of thousands of known genes—to carry out a technique called gene expression profiling, NIAMS-supported researchers will analyze thousands of genes in the blood, fluids, and tissues of children newly diagnosed with various types of pediatric rheumatic diseases. Identifying gene expression patterns—groups of genes that are “turned on”—for different types of childhood arthritis will help to improve diagnosis and to predict disease severity for affected children.
Two separate clinical trials are examining therapeutic interventions in children with JRA. One trial is investigating osteopenia (reduced bone mass), a frequent complication of JRA. This clinical trial measures the effectiveness of daily oral calcium supplementation to increase total body bone mineral density.
The long-term goal is to determine the safety and effectiveness of current and new biologic and pharmacologic treatments as alternative treatments to calcium in those JRA patients with osteopenia.
Marfan syndrome is an inherited disorder caused by a mutation in the fibrillin gene. This mutation causes the tendons, ligaments, and other connective tissues in the body to weaken. Marfan syndrome can affect the heart, skeletal system, eyes, and other organs in the body and symptoms range from mild to severe. The NIAMS recently awarded a program project grant to develop a multi-site translational research program in Marfan syndrome. The long-term goal of this program is to translate basic research in matrix biology into treatment strategies for individuals with Marfan syndrome and related disorders of connective tissue. The program will utilize a comprehensive and multidisciplinary approach that integrates the scientific interest and expertise of four leading laboratories in this and related research fields. Researchers will study genetically engineered mouse models of Marfan syndrome to uncover the abnormal cellular activities that contribute to this disorder and will translate this new knowledge into more effective therapies.
Significant Ongoing Rare Diseases Research Initiatives
Scleroderma, often referred to as a single disease, is actually a symptom of a group of diseases that involves the abnormal growth of connective tissue, which supports the skin and internal organs. In some forms of scleroderma, hard, tight skin is the extent of the disease. In other forms, however, the problem goes much deeper, affecting blood vessels and internal organs such as heart, lungs, and kidneys. A NIAMS-funded project is using a unique sample set—lung tissue from scleroderma patients undergoing lung transplant surgery as well as lung tissue from unused donor lungs—to facilitate investigation into the cellular changes that cause the hardening of the lungs. Other NIAMS-supported researchers are examining the cellular and molecular processes of scleroderma, cell transfer between mother and child, and the development of innovative therapies.
Juvenile Systemic Lupus Erythematosus
In the area of childhood lupus, NIAMS-supported researchers are currently conducting a large, controlled study to assess the ability of statins (cholesterol-lowering agents) in preventing or delaying progression of cardiovascular disease in children with lupus. This research study involves 20 centers from the Pediatric Rheumatology Research Network in establishing the largest cohort of pediatric lupus patients ever prospectively studied. Approximately 15 percent of patients have been enrolled and baseline data analysis is currently under way.
The NIAMS is collaborating with several other NIH components to boost muscular dystrophy research. Along with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), the NIAMS is supporting one of three cooperative research centers focused on muscular dystrophy. NINDS and NICHD are also supporting one center each. Researchers at two of the centers are studying gene and/or stem cell therapies to treat muscle diseases, in particular Duchenne muscular dystrophy. A third center is examining skeletal muscle at the cellular and molecular levels to determine which factors might contribute to problems in the muscular dystrophies. This center is focusing on myotonic and facioscapulohumeral muscular dystrophies. Supplemental funding for these centers is being provided by the Muscular Dystrophy Association.
Neonatal Onset Multisystem Inflammatory Disease
Neonatal onset multisystem inflammatory disease (NOMID) is a rare, chronic, inflammatory disease that leads to major disability in affected children. Intramural researchers at the NIAMS have identified the genetic cause for this disease. Research suggests that a pro-inflammatory cytokine (a protein involved in the body’s immune response), IL-1, could be contributing to the disease manifestations of NOMID. The NIAMS has initiated a multicenter study to evaluate the safety and efficacy of anakinra, a drug that blocks the activities of IL-1. Results in children with NOMID indicate that IL-1 blockade is highly efficacious in improving clinical signs and symptoms of this disease including fevers, rash, joint pain, headaches, and conjunctivitis (inflammation of the eye) and in lowering inflammatory markers of disease activity. In addition, anakinra crosses the blood brain barrier and has led to improvement in inflammation in the brain in a number of children.
Vasculitis Clinical Research Consortium
The NIAMS, in collaboration with the NIH Office of Rare Diseases and the National Center for Research Resources, is supporting the Vasculitis Clinical Research Consortium (VCRC), a part of the NIH Rare Diseases Clinical Research Network. Four centers comprise the VCRC and will serve as the focal points for vasculitis research, both domestically and internationally, for patients and researchers. One goal of the research is to develop new biomarkers of vasculitis disease activity.
Rare Disease-specific Scientific Conferences, Symposia, and Meetings
In collaboration with the NIH Office of Rare Diseases, the NIAMS provided support for the meeting, “Mild OI—Toward Better Understanding and Treatment.” Osteogenesis imperfecta (OI) is a genetic disorder characterized by bones that break easily, often with little or no apparent cause. Many significant medical problems associated with mild OI, such as hearing loss, spinal involvement with compression fractures, and neurological impairment, may appear only in adult life. For patients with mild OI, the intensive, multi-disciplinary health care that has typically focused on the more severe pediatric forms of OI is seldom available. This meeting brought together a group of international experts in the clinical care of individuals with OI to help identify the major health care issues that face people with mild OI, to better define the natural history of mild OI, and to examine the genetic components of this disease.
Pseudoxanthoma Elasticum (PXE) is a systemic inherited disorder that affects the elastic tissue in the skin, eyes, and cardiovascular system, and it can result in severe and even fatal problems in affected individuals. In the past several years significant progress has been made in the basic understanding of the genetics of PXE and the structural components affected by PXE. These advances, however, have highlighted a lack of information linking genetic and molecular advances and the development of PXE. In FY 2004, the NIAMS provided support for a meeting to bring together investigators from various fields of research to discuss how relevant advances in biology, metabolism, genetics, and epidemiology may help to bridge this information gap. The meeting was co-sponsored by the NIH Office of Rare Diseases, the National Eye Institute, the National Human Genome Research Institute, and PXE International, a nonprofit foundation that advances research on PXE.
The NIAMS recently provided support for the “International Workshop for Scleroderma Research.” This workshop focused on basic research related to the pathogenesis of scleroderma. Scientific sessions covered autoimmunity, genetics, gene expression, vascular injury, animal models, fibrosis, and matrix metabolism. Clinically related areas such as novel therapeutics and development of measures of disease were also covered. The workshop brought together investigators in scleroderma from throughout the world along with prominent researchers in related disciplines.
Fibrosis, or skin thickening, is a feature of several rheumatic, musculoskeletal, and skin diseases, including scleroderma. The scientific meeting, “Pathogenic Mechanisms of Fibrosis: Search for Common Ground,” brought together internationally recognized leaders and experts in the field of fibrosis to provide a forum for the cross-fertilization of basic science approaches and clinically relevant problems. The primary focus was on common mechanisms and pathways of fibrosis.
Activities with Voluntary Rare Diseases Organizations to Stimulate Research
Health Partnership Program
The NIAMS Health Partnership Program (HPP) has made significant steps in achieving the mission of understanding health disparities in minority populations and providing direction for improving the health status and health outcomes of those communities affected. The HPP is a community-based research initiative that operates through a collaborative effort between NIAMS and Washington, DC, area community partners. Through this partnership, initiated in February 2000 with the program, the HPP has established the NIAMS Community Health Center (CHC), which is located in a medically underserved minority community in Washington, DC. This site serves as a focal point for many of the program’s activities, including the clinical study, The Natural History Study of Rheumatic Diseases in Minorities. In order to extend services to other communities the NIAMS has recently started providing consultation services for patients with rheumatic disease in a separate clinic in southeast Washington, DC.
Education Activities on Rare Diseases for the Researchers, Public, and the Health Care Providers Communities
The NIAMS is committed to a comprehensive program of information dissemination to patients and to their health care providers. Research advances are of limited value if they never reach the arena of health care, and they miss the goal of improving public health for all Americans. To this end, the NIAMS has updated several publications on rare diseases, including booklets in its Questions and Answers series on Behcet’s disease and lichen sclerosis and information packets on pemphigus and other blistering skin disorders, amyloidosis, polymyositis/dermatomyositis, and sweating disorders. In addition, the NIAMS has expanded its collection of Spanish language publications by adding El Sindrome de Marfan (Marfan syndrome).
NIH Senior Health Web Site
Through the NIH Osteoporosis and Related Bone Diseases National Resource Center, operated by the NIAMS, the Institute is currently developing a module on Paget’s Disease for the NIH Senior Health Web site. This module will provide information on symptoms and complications, diagnosis, treatment, and research on this rare bone disease. The Institute is also updating two publications for health professionals working with patients who have osteogenesis imperfecta: Therapeutic Strategies for Osteogenesis Imperfecta: A Guide for Physical Therapists and Occupational Therapists, and Osteogenesis Imperfecta: A Guide for Nurses. These publications will be available in print and included on the Institute’s pediatric rheumatology CD-ROM.
Pediatric Rheumatology CD-ROM
The NIAMS, in collaboration with the Arthritis Foundation, is producing a pediatric rheumatology CD-ROM to provide pediatric health professionals with access to the latest information on pediatric rheumatic diseases and to encourage early diagnosis and treatment. Disease topics include heritable disorders of connective tissue, scleroderma, and osteogenesis imperfecta.