STATEMENT OF CAROL ANNE PEREZ, EXECUTIVE DIRECTOR,

FACIOSCAPULOHUMERAL SOCIETY (THE FSH SOCIETY) BEFORE THE

UNITED STATES HOUSE OF REPRESENTATIVES COMMITTEE ON APPROPRIATIONS, SUBCOMMITTEE ON LABOR, HEALTH AND HUMAN SERVICES AND EDUCATION AND RELATED AGENCIES REGARDING FISCAL YEAR 2005 APPROPRIATIONS FOR NIH RESEARCH AND PROGRAMS FOR RESEARCH ON FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD) APRIL 29, 2004

Mr. Chairman, it is an honor to submit this testimony to you today.

My name is Carol Anne Perez, of Lexington, Massachusetts, and I am testifying as Executive Director of the FacioScapuloHumeral Muscular Dystrophy Society (FSH Society, Inc.) and as an individual who has lived with the devastating facioscapulohumeral muscular dystrophy (FSHD) disorder for nearly seventy years.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most prevalent form of muscle disease. FSHD is a neuromuscular disorder that is transmitted genetically to approximately 1/20,000 people. Conservatively, it affects 14,000 persons in the United States. For men, women, and children the major consequence of inheriting FSHD is progressive and severe loss of all skeletal muscles gradually bringing weakness and reduced mobility. The usual pattern is of initial noticeable weakness of facial, scapular and upper arm muscles and subsequent weaknesses of other skeletal muscles. Retinal and cochlear disease, as well as mental retardation, can be associated with FSHD. Many with FSHD are severely physically disabled and spend the last 30 years of their lives in a wheelchair. The toll and cost of FSHD physically, emotionally and financially are enormous. FSHD is a life long disease that has an enormous cost-of-disease burden and is a life sentence for the innocent patient and involved persons and their children and grandchildren as well. As a human services professional, wife, mother and grandmother, I am now in a wheelchair due to the effects of FSHD.

In accordance with its primary purpose of serving the FSHD community, both in the United States and abroad, the FSH Society, through outreach at home and international networking, has brought together more than 3,000 FSHD-affected families committed to working cooperatively. From the moment of their introduction into the FSH Society, these families, and, in many instances, their friends are bonded with their fellow members both by their common knowledge of what it is to live with FSHD and by the ardent desire they all feel to be part of a concerted effort to discover how to treat the disease and, ultimately, to cure it.

People who have FSHD must cope with continuing, unrelenting, unpredictable and never-ending losses. The most unlucky, those who are affected from birth, are deprived of virtually all the ordinary joys and pleasures of childhood and adolescence. But no matter at which stage of life the disease makes itself known, there is never after that any reprieve from continuing loss of physical ability, or ever for a moment relief from the physical and emotional pain that FSHD brings in its train. Every morning, FSHD sufferers wake up to face the reality that neither a cause for their disease nor any treatment for it has yet been found.

Insidiously and systematically, FSHD denies a person the full range of choices in life. FSHD affects the way you walk, the way you dress, the way you work, the way you wash, the way you sleep, the way you relate, the way you parent, the way you love, the way and where you live, and the way people perceive and treat you. You lose the ability to smile, hold a baby in your arms, close your eyes to sleep, run, walk on the beach, or climb stairs. Each new day brings renewed awareness of the things you may not be able to do the next day. This is what life is for tens of thousands of people affected by FSHD worldwide.

Through the FSH Society, FSHD patients have found ways to be useful to medical and clinical researchers working on their disease. The FSH Society acts as a clearinghouse for information on the FSHD disorder and on potential drugs and devices designed to alleviate its effects. It fosters communication among FSHD patients, their families and caregivers, charitable organizations, government agencies, industry, scientific researchers, and academic institutions. It solicits grants and contributions from members of the FSH Society, and from foundations, the pharmaceutical industry, and others to support scientific research and development. It makes seed grants and awards to qualified post doctoral research applicants.

In less than five years, the FSH Society has raised more than $1 million for research and has invested it in two dozen innovative research programs internationally. The FSH Society's Scientific Advisory Board is composed of international experts whose awareness of current FSHD research ensures both that new research is not duplicative but complementary and that it will fill gaps in existing knowledge. The FSH Society's work in education, advocacy, and training has led to the start of increased funding in the United States and abroad. It was a key participant in drafting the Muscular Dystrophy Community Assistance Research and Education Act of 2001 (MD CARE Act) which in the United States mandates research and investigation into all forms of Muscular Dystrophy.

The Appropriations Committees in both the U.S. House and the U.S. Senate have repeatedly instructed the National Institutes of Health (NIH) to enhance and broaden the portfolio in FSHD and muscular dystrophy in general. The NIH accounting for the total overall NIH and the subset of muscular dystrophy appropriations in millions of dollars for the past five years follows:

National Institutes of Health (NIH) Appropriations History

Source: NIH/OD Budget Office & NIH CRISP Database On-line

(Dollars in millions)

Fiscal NIH Overall MD Research MD % FSH Research FSHD %                FSHD %

Year Dollars Dollars of NIH Dollars of MD of NIH

2000 $17,821M $12.6M 0.071% $0.4M 3.18% 0.0022%

2001 $20,458M $21.0M 0.103% $0.5M 2.38% 0.0024%

2002 $23,296M $27.6M 0.118% $1.3M 4.71% 0.0056%

2003 $27,067M $39.1M 0.144% $1.5M 3.83% 0.0055%

2004E $27,887M $40.2M 0.144% $2.7M 6.71% 0.0097%

Due to major initiatives from the volunteer health agencies and the extramural community of researchers, FSHD research at the NIH and funding through the NIH is moving ahead at a steady pace though seemingly incredibly slow for those of us suffering from FSHD. Notwithstanding these positive changes at the NIH as well as major cooperative initiatives from the volunteer health agencies and the extramural community of researchers, we realize that major changes are slow but we are hopeful that this year the NIH will initiate new and increased funding for FSHD.

Funding for FSHD as related to the entire muscular dystrophy portfolio is not keeping pace with all muscular dystrophy. FSHD is the third most prevalent form of muscle disease and a common muscular dystrophy. Yet, in 2003 it received only 3.83 percent of the total NIH wide muscular dystrophy portfolio and that number has improved slightly to an estimated 6.71 percent for fiscal year 2004.

Mr. Chairman, as you know, the National Institute of Child Health and Human Development (NICHD), the National Institute of Arthritis and Musculoskeletal Disorders (NIAMS), and, the National Institute of Neurological Disorders and Stroke (NINDS) are three of the National Institutes of Health (NIH) institutes called upon by the Muscular Dystrophy Community Assistance Research and Education Act of 2001 (MD CARE Act) to develop a research plan for muscular dystrophy (MD) research and education conducted through the National Institutes of Health. Certainly, other NIH institutes will be called into action where appropriate such as NHLBI, NEI, NIA, NIMH, NHGRI, NCRR, FIC, and OD.

National Institutes of Health (NIH) Muscular Dystrophy and FSHD Appropriations History

Source: NIH/OD Budget Office & NIH CRISP Database On-line

(Dollars in millions)

Fiscal Total NIH NIAMS NINDS NICHD NIH wide

Year Dollars on MD Dollars on MD Dollars on MD Dollars on MD Dollars on FSHD

2000 $12.6M $4.8M $4.9M $1.2M $0.4M

2001 $21.0M $9.2M $8.2M $0.5M $0.5M

2002 $27.6M $11.1M $9.8M $0.6M $1.3M

2003 $39.1M $15.5M $13.2M $4.5M $1.5M

2004E $40.2M $15.9M $13.5M $4.7M $2.7M

2005E $41.0M $16.3M $13.7M $4.8M $2.8M

In fiscal year 2004 year-to-date, the National Institute of Child Health and Human Development (NICHD) does not have a single research grant or project directly focused or covering FSHD. NICHD is spending $0 out of an estimated $4.7M on directly titled FSHD projects. NICHD is spending 0 percent of its muscular dystrophy (MD) budget on FSHD. Some of the most seriously affected FSHD cases are children with symptoms from infancy.

In fiscal year 2004 year-to-date, the National Institute of Arthritis and Musculoskeletal Disorders (NIAMS) is funding two directly titled projects on FSHD and the NIH FSHD Research Patient Registry. The directly titled grants and contracts are 5-R21-AR-48318-03 at $198,000, 5-R21-AR-48327-03 at $125,000, and, 3-N01-AR-02250-004 at $175,754. Directly focused and titled research grants on FSHD actually decreased in FY2004 due to the expiration of a third R21 and no new directly titled and relevant projects are being funded.

No new projects directly titled and focused on FSHD have been initiated in the past three years. Not a single one. The total direct expenditure from the lead institute on FSHD muscular dystrophy, the NIAMS, was $498,754. The NIAMS is spending 3.1 percent of its total muscular dystrophy budget on FSHD. Something is definitely and clearly wrong with this picture as the NIAMS has an extremely low ratio of FSHD to muscular dystrophy funding as the lead institute.

In contrast, in fiscal year 2004 year-to-date, the National Institute of Neurological Disorders and Stroke (NINDS) is spending 16.3 percent of its total muscular dystrophy budget on FSHD. The NINDS is funding seven directly titled projects on FSHD and the NIH U54 Cooperative Research Center at the University of Rochester. The NINDS is currently funding four R21 style grants, two R01 style grants, the U54 MD CRC, and the NIH FSHD Research Patient Registry. NINDS has increased its portfolio by one R21 grant, two R01 grants and one U54 Cooperative Research Center in the last year. The NINDS has shown an uncanny ability to move the field of FSHD research ahead with many excellent research projects as well as sponsoring the unprecedented NIH Wellstone Cooperative Research Center. The second request for applications for the next round of Wellstone Muscular Dystrophy Centers has just been announced. The late Senator Wellstone would have been proud of the achievements made to date in the area of muscular dystrophy and it is befitting and appropriate that the muscular dystrophy research centers create a living memory for his substantial efforts.

While it is recognized that research grants, grant applications and interest of the researchers may ebb and flow, we are seriously concerned and perplexed with the total lack of presence by the NICHD in FSHD and the dip in direct FSHD support by the NIAMS, ostensibly the lead institute at the NIH, on muscular dystrophy. The NIAMS has 3.1 percent of its dystrophy portfolio allocated to FSHD, the third most prevalent dystrophy. The NIH says that they are not receiving enough grants applications for FSHD. The NIH needs to recognize that there is a systemic funding problem as relates to FSHD. The volunteer health agencies and extramural community of researchers have done everything in our power to grow the area of research and to promote new researchers and research projects. The extramural research community needs to know from the NIH that there are specific grant mechanisms and announcements with money associated.

No gene has yet been found for FSHD. The NINDS, NIAMS, NICHD and relevant NIH institutes understand that FSHD is a unique disease and that there are exciting breakthroughs around understanding the molecular basis of FSHD. The scientific opportunities are numerous: elucidation of the molecular pathogenic pathways of the FSHD disease is instrumental to improved patient diagnosis, counseling, management and treatment. It is now generally accepted that FSHD is caused by a deletion (contraction) of D4Z4 repeats on the chromosome 4q. New mutations are frequently encountered and approximately half of cases seem to be due to somatic rearrangements. An interesting gender difference in disease expression in mosaic patients – males are more susceptible to disease - suggest a hormonal modulation of the phenotype. FSHD is associated with a genomic rearrangement and it is unlikely that the D4Z4 deletion structurally compromises a putative FSHD gene. Evidence strongly supports a model in which the D4Z4 contraction induces a change in the chromosomal environment, more specifically the chromatin structure, which in its turn modulates the gene expression of gene(s) in cis or in trans. This may occur by a spreading or looping mechanism, or more speculatively, by a mechanism similar to transvection as chromosome ends of 4q and 10q that seem to exhibit a higher pairing frequency and other forms of cross talk. However, identification of the exact molecular mechanism and the crucial target gene(s) has still to be done. There is increasing evidence for FSHD-specific changes in the chromatin structure and the histone code. Most arguments suggest a unique (novel) pathogenic mechanism behind FSHD. Elucidation of this intricate molecular network is instrumental to the development of evidence-based treatment (and preventive) strategies.

Researchers are available and the interest is there. Top priority research targets and areas for investigation have been given by FSHD research experts to the NIH for consideration as the NIH research plan is developed. They include: 1.) Detailed characterization of individual candidate genes on chromosome 4q; 2.) Identification of the difference between 4qA and 4qB; only short 4qA is causing FSHD; 3.) The molecular causes and consequences of the exchange between 4q and 10q; 4.) Chromatin structure and nuclear organization histone code; methylation, acetylation etc.; 5.) Establishment of the gene expression modulation on chromosome 4q and genome-wide; 6.) Development of functional models in vitro (cellular) and in vivo (transgenic); 7.) Implementation of systems biology (integrated-omics and bioinformatics) to reveal molecular and metabolic pathways involved; 8.) Harmonize and standardize molecular diagnostic procedures; 9.) Systematic ascertainment and characterization of (homogenous) patient populations for clinical trials; 10.) Generation of tools and reagents to monitor (pharmacological, training, or gene therapy) interventions; 11.) Identification of additional FSHD loci and genes.

More than ten years ago, the FSH Society asked the NIH what we could do to work with them to develop research programs in FSHD. We were told that we needed to go out and find researchers interested in working on FSHD and encourage them to apply for the NIH grants. We did that but the NIH has consistently rejected funding for these researchers. In several instances, the reviews were clearly incorrect and uninformed e.g. stating the gene for FSHD had already been found. Our researchers’ applications were often rejected since they were proposing new and novel solutions to the complex molecular problem that FSHD presents. The FSHD chromosomal deletions causing the disease have no immediately associated or imbedded genes. The FSH Society, asked the NIH to provide a mechanism to fund innovative research on FSHD when our researchers, who have applied for research funding for FSHD, were rejected.

We, the FSH Society, as patients, raised the funds to support seed grants to encourage innovative researchers to begin to research the complexities of FSHD. In 1998, we established an advisory scientific review board of outstanding international clinicians and researchers who are skilled and knowledgeable in the current clinical research and laboratory research on muscular dystrophies and we funded our first grants. We have funded 24 research projects to date with a minimum of resources. In six years, our researchers on our small seed grants made amazing breakthroughs on FSHD in understanding the mechanisms in FSHD molecular genetics (these mechanisms have far ranging applications to other disorders). The NIH, particularly NIAMS, continues to reject our researchers’ proposals

We, the FSH Society, as patients, helped write the legislation mandating research on FSHD and all other dystrophies. The NIH continues to refuse our researchers’ applications for funding and continues to list research grants completely unrelated to FSHD as their contribution to meeting the requirements that you have mandated for FSHD research funding. This is unconscionable that the leading institutes do not fund these innovative and extraordinary projects.

We request that you ask the NIH why, when with the minimal resources available to the FSH Society and in six years, we have developed a program that has great promise, and we have developed the researchers and identified the next steps in research, the NIH still has not taken your lead to make a difference. We have done all that has been asked of us and our patience is exhausted.

Congress has been very generous with the NIH. Congress has repeatedly mandated more effort in muscular dystrophy research in general and FSHD research in particular. But this is not happening. We ask Congress to continue its support for the overall budget increases for the NIH as this will alleviate the serious budget constraints faced by this most remarkable federal agency. We also ask that Congress request an explanation from the program staff and Directors of the NIH NIAMS and NICHD for the inability to do better in the area of FSHD despite repeated Congressional requests. We implore Congress to request the NIH to specifically build the research portfolio on FSHD through all available means, including re-issuing specific calls for research on FSHD at an accelerated rate, to make up for historical and present neglect.

Mr. Chairman, We believe the Committee should explore why muscular dystrophy in general and FSHD in particular has been left behind in the great rise in research support at the NIH. Frankly, we are frustrated that amid a huge increase in funding and strong unambiguous expressions of Congressional support, the NIH commitment in facioscapulohumeral muscular dystrophy (FSHD) is so feeble.

Mr. Chairman, again, thank you for providing this opportunity to testify before your Subcommittee.