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Witness appearing before the Senate Subcommittee on Labor-HHS-Education Appropriations
April 8, 2003 (historical)
Stephen I. Katz, M.D., Ph.D., Director
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Kerry N. Weems, Acting Assistant Secretary for Budget,
Technology and Finance, HHS
William R. Beldon, Acting Deputy Assistant Secretary for Budget, HHS
Mr. Chairman and Members of the Committee:
I am pleased to present the President's budget request for the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The fiscal year (FY) 2004 budget includes $502.778 million, an increase of $17.005 million over the FY 2003 enacted level of $485.773 million comparable for transfers proposed in the President's request.
The budget increases over the last few years have made a tremendous difference in the studies we have been able to launch, particularly in clinical research including clinical trials in a wide variety of diseases as well as the expansion of vital scientific infrastructure in a creative way. As stewards of these funds, we have worked with a wide range of advisers, both from the scientific community and from the lay public, to ensure that we target areas of greatest scientific opportunity. In addition, we worked to undertake studies that could either be done solely or better by the Federal government. I am pleased to be able to share highlights of some of the stories of progress and promise that have resulted from our investments in medical research.
One of the priority areas in the new NIH Roadmap Initiative is the development of public/private partnerships. The NIAMS has had a number of positive experiences in this area, and I will mention two ongoing examples. The first is the Osteoarthritis Initiative. Our Institute partnered with the National Institute on Aging and several other NIH components as well as with three pharmaceutical companies in launching this public/private partnership aimed at developing clinical research resources that support the discovery and evaluation of biomarkers and surrogate endpoints for osteoarthritis clinical trials. This seven-year project is being undertaken by four clinical sites and one data coordinating center, and this consortium will likely serve as a model for future endeavors that link the public and private sectors.
The second partnership involves the NIH and the Muscular Dystrophy Association (MDA). The NIH has been actively engaged in implementing the mandates of the MD-CARE Act, and has worked closely with representatives of the muscular dystrophy (MD) research and patient communities in this effort. Specifically, the NIAMS, NINDS, and NICHD have partnered to issue new research solicitations for MD cooperative research centers, and for developmental planning grants for future centers. In addition, we are developing an initiative to support the training of basic and clinical researchers to study muscular dystrophy. To underscore the importance of stimulating and supporting further work in this area, the NIH has established an MD Research Task Force, which includes NIH scientific staff, as well as researchers, clinicians, and patient representatives. This group will help ensure that we pursue all promising opportunities to boost MD research and training, and it will also complement the work of the newly established inter-agency Muscular Dystrophy Coordinating Committee, which was called for in the MD-CARE Act.
One of the most active and productive areas within the Institute's research portfolio is in the muscular dystrophies - a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement. Research advances from NIAMS investments in this area include: (1) the finding that people with facioscapulohumeral muscular dystrophy (FSHD) have an exclusive association with one of the two different forms of the chromosomal region linked to the disease. This work may lead to a better understanding of the instability of the genetic locus associated with FSHD. (2) the discovery of how to reverse muscle degeneration in a mouse model of Duchenne muscular dystrophy, a genetic disorder in which muscle cells become progressively more damaged and die. Scientists have devised a way to revitalize wasting muscle by using a special viral carrier to introduce the missing dystrophin gene into the diseased muscle tissue - a finding that could eventually lead to gene therapies for patients with Duchenne muscular dystrophy. (3) the report that a faulty gene is key to understanding myotonic dystrophy. The genetic defect affects the conductance of electrical signals, resulting in delayed muscle control. (4) the isolation of muscle-generating stem cells that can improve muscle regeneration and deliver the missing protein dystrophin to damaged muscles in a mouse muscular dystrophy model. These results signal that some of the major obstacles to stem cell transplantation may be overcome, resulting in more effective treatments for muscular dystrophy and other muscle-related diseases. and (5) the creation of a new animal model that has been labeled a "marathon mouse," which expresses an energy-metabolizing protein that increases the proportion of particular muscle fibers that give distance runners their muscular stamina. Further work in this area could benefit research efforts against muscle-wasting diseases like the muscular dystrophies.
Systemic Lupus Erythematosus
Some of the most promising research results in our mission areas have come from the ability of researchers to apply the explosion of information in genetics and genomics. One example of this is the very recent research report that a particular genetic "signature" has been linked to the blood of patients with severe systemic lupus erythematosus (SLE or lupus). A team of scientists supported by the NIAMS, other parts of the NIH, and the private sector (the Minnesota Lupus Foundation and the Alliance for Lupus Research) has discovered a genetic "signature" present in some patients with lupus who develop such life-threatening complications as blood disorders, central nervous system damage, and kidney failure. These researchers analyzed thousands of genes in the blood of patients with lupus, and, surprisingly, 14 of the thousands of genes studied were linked to a subset of lupus patients with severe disease. These 14 genes are associated with a complex family of proteins involved in the regulation of immune responses, and these findings provide strong support for developing new therapies to block the affected pathways in patients with severe lupus, as well as for identifying patients most likely to benefit from these new therapies.
I want to also mention an important new clinical trial that we launched in children with lupus. The trial is designed to test the efficacy 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.
Bone and Other Musculoskeletal Diseases
One dimension of the NIH Roadmap Initiative is translational research, and we know that translating the results of basic bone biology research into therapies that prevent or treat musculoskeletal diseases can have a very significant impact on public health. Development and maintenance of a healthy skeleton depends on interactions between bone and bone marrow, blood vessels, and even the central nervous system. Understanding these complex interactions will depend on studies employing genetic and genomic tools, including NIAMS-supported efforts in animal models that are expected to translate into insights guiding the development of new preventive and therapeutic approaches to conditions such as osteoporosis. In recent advances, a variety of pharmacological agents and biochemical factors, some already familiar in other contexts, has been found to have unexpected effects on bone mass. For example, the actions of the cholesterol-lowering drugs called statins, the hormone leptin (originally identified as important for controlling obesity), and nitric oxide (best known for its effects on the heart and blood vessels) all provide clues to ways that new therapies might improve bone health. In addition, studies of the genetics of bone mass are increasingly productive, including reports of a gene that was previously unsuspected of playing any role in bone emerging as a possible key to restoring bone in cases of osteoporosis.
Research that has direct applicability to daily life of affected individuals has determined that limb reconstruction and amputation after trauma to the lower leg result in similar outcomes in terms of function. We anticipate that the findings of this study will help surgeons and patients make better informed decisions when choosing between reconstruction (limb salvage) or amputation of a limb that has been severely damaged. With a look to the future, a large United States/Canada cooperative project is now underway to resolve differences of opinion on the best way to repair the fracture of the tibia - the most common long bone fracture in the human body. Factors that will be considered in determining which of the groups being studied has a more successful outcome include how soon patients return to work and their general health status and quality of life. Finally, plans are underway for an NIH Consensus Development Conference on Primary Knee Replacement in December 2003 to address the issues that exist in this area, to review the current state of the science, and to identify directions for future research.
NIAMS-supported researchers recently reported exciting and promising results from their gene therapy studies in the recessive form of the devastating blistering skin disease dystrophic epidermolysis bullosa. This disease is caused by the absence of a specific gene, and researchers used a particular enzyme as the base for gene transfer. The researchers were successful in stably integrating the DNA from the missing gene into genomes of cultured skin cells from four patients with this inherited skin disease. The skin that was developed using these cells displayed stable correction of the hallmark features of this disease. These results establish a potential practical approach to nonviral genetic correction of severe human genetic disorders that require stable genomic integration of large DNA sequences.
The Institute has recently called on scientific experts and lay representatives to help us in three particular areas of skin diseases research: (1) In response to FY 2002 Congressional language, the NIAMS sponsored the "Workshop on the Burden of Skin Disease" in September 2002, to discuss the elements that comprise the burden of skin diseases and their impact on public health and daily living; current knowledge and data-collection instruments, and how to access the data more effectively; and future data needs and instruments for facilitating the collection of the data. The recommendations from this workshop are being reviewed by the Institute to determine the need and path for future initiatives in this area. The lessons learned from this workshop can serve as a paradigm for other areas - all of which share the challenge of defining the burden of a disease on an individual, the family, the workplace, and society as a whole. (2) The NIAMS teamed with the National Alopecia Areata Foundation in sponsoring the Fourth International Research Workshop on Alopecia Areata in November 2002, bringing together investigators from around the country for an exchange of recent findings in alopecia areata and related fields of hair biology. Results of this workshop will guide future research in this field. (3) The Institute is planning a workshop on immune modulation in the treatment of skin diseases, which will include new treatments for psoriasis, atopic dermatitis, autoimmune bullous diseases, and other skin diseases. The workshop will focus on trying to understand how some new treatments are actually working so that we may better understand the mechanisms underlying these diseases.
In research related to health disparities, there are four efforts that I want to highlight: (1) The NIAMS continues to support the diversity initiative it has created and developed over the last few years - the Health Partnership Program, a collaborative community-based effort in Washington, D.C., that is directed at developing research programs to understand and address health disparities in rheumatic diseases in African American and Hispanic/Latino communities. (2) Differences have been documented in the damage caused by lupus in studies of Hispanic, African American, and Caucasian individuals with this disease. The proportion of patients who had any organ damage was higher among Hispanics than among the other two groups, confirming the greater negative impact of lupus among members of this ethnic group. The association of organ damage with poor coping skills was reported for the first time, and it suggests that approaches designed to modify patients' behaviors and attitudes to their illness could reduce the damage to the body caused by lupus. (3) Research suggests that women with lupus are at increased risk for both clinical osteoporosis and cardiovascular complications at a much younger age, and more aggressive control of the risk factors for these complications is needed to prevent these conditions in women with lupus. (4) Social experience has been shown to influence joint replacement decisions; that is, when people think about having a hip or knee replaced, knowing someone who has had the surgery may influence their decision. A recent study funded by the NIAMS and the Robert Wood Johnson Foundation suggested that one reason African Americans may be less likely than Caucasians to seek joint replacement surgery, a procedure that makes a significant difference in alleviating pain and improving function of severely affected individuals, is because they know fewer people who have had this procedure.
We are proud of the advances that scientists supported by the NIAMS have achieved and we are excited about initiatives that we have launched. Patients and their families are looking to us with hope and anticipation for answers to what causes their diseases, as well as how their diseases can be better treated and even prevented. We are confident that public health in general as well as daily life for affected individuals in particular will benefit from NIAMS research in the extensive and diverse array of chronic diseases within our mission areas of bones, joints, muscles, and skin.
I would be happy to answer any questions.