Testimony of Daniel Paul Perez, President & CEO of the FSH Society

Before the Appropriations Subcommittee on Labor, Health and Human Services,

Education and Related Agencies on the Subject of FY2007 Appropriations for

National Institutes of Health Research on FSH Muscular Dystrophy April 3, 2006

Chairman Specter, Senator Harkin and members of the Subcommittee, I am Daniel Perez, President & CEO of the FSH Society. The FSH Society is a non-profit volunteer health agency organized by patients for patients with facioscapulohumeral muscular dystrophy (FSHD). Our purpose is to be a resource for individuals and families with FSH muscular dystrophy (FSHD), represent them and advocate on their behalf. On behalf of the FSH Society and its members, thank you for this opportunity to testify.

FSHD is the third most prevalent form of muscle disease and the second most prevalent adult muscular dystrophy. It affects 1/20,000 people. For men, women, and children the major consequence of inheriting FSHD is a lifelong progressive and severe loss of all skeletal muscles. The FSH Society was created because of a need for a comprehensive resource for FSHD individuals and families. A world leader in combating muscular dystrophy it has provided well over a million dollars in seed grants to pioneering researchers worldwide and created an international collaborative network of patients and researchers. The Society relies entirely on private grants, donations and philanthropy. Since our establishment in 1991, our major focus has been to help facilitate federal research agencies such as the National Institutes of Health (NIH) grow funding and programs for FSHD research. The Society has submitted 28 written and five oral testimonies to Senate and House Appropriations Subcommittees on Labor, Health, Human Services and Education on the need for more NIH funding on FSHD.

The NIH often applauds the effort and dedication of the Society in expanding research efforts in FSHD and bringing additional attention to this dystrophy. We commend the Director of the NIH, Dr. Elias Zerhouni, for the significant efforts made by his agency in muscular dystrophy. Between 1987 and 2005, the overall NIH funding for dystrophy increased from $4.6 million to $39.3 million. Since 2000, the FSHD budget has increased from $400,000 to $2.1M (FY2006 estimated). We applaud Dr. Stephen I. Katz, Director, National Institute of Arthritis and Musculoskeletal Disorders (NIAMS) and Chairman of the Muscular Dystrophy Coordinating Committee (MDCC), and John D. Porter, Program Director Muscular Dystrophy, National Institute of Neurological Disorders and Stroke (NINDS) and Executive Secretary MDCC, for their extraordinary comprehension, accuracy and for the speed in which the NIH Action Plan for Muscular Dystrophy was researched, compiled, written, and approved. The NIH is making significant investments to understand muscular dystrophy research needs and has made excellent choices in recruiting program staff with the ability to understand the extremely complex nature of muscular dystrophy. However, to this day, the NIH reports difficulty in growing and expanding its FSH muscular dystrophy research portfolio and in receiving sufficient numbers of investigator-submitted applications of high quality.

The MD-CARE Act, P.L. 107-84

Congress enacted The Muscular Dystrophy Community Assistance, Research and Education Amendments of 2001 (the MD-CARE Act, Public Law 107-84) that was signed into law on December 18, 2001. Both the Senate and House acted with force and clarity to mandate the NIH and other applicable federal agencies, to immediately expand and intensify research on all forms of muscular dystrophy. The MD-CARE Act declared that: 1.) the Director of the NIH work with the Directors of NIAMS, NINDS and NIH National Institute of Child Health and Human Development (NICHD) to expand and intensify research on all nine types of dystrophy described in the Act; 2.) Centers of excellence for research should be established for all nine types of dystrophy; 3.) a MDCC with two-thirds government and one-third public members be established to coordinate activities across NIH and other national research agencies on all forms of dystrophy; and; 4.) the MDCC to submit a research action plan for conducting, and supporting research and education for all nine types of dystrophy. The MD-CARE Act also requires annual updates on research funding amounts by the Department of Health and Human Services (DHHS) for Duchenne, Myotonic, FSHD and other muscular dystrophies.

In August 2004, the MDCC submitted an initial report for the NIH Muscular Dystrophy Research and Education Plan to Congress which was put through a more intensive planning process that involved external scientific experts in the field of muscular dystrophy and muscle disease. This detailed version of the MDCC “Action Plan for the Muscular Dystrophies” was submitted to Congress in December 2005.

FSHD is prominently and well represented in the five sections of the NIH “Action Plan for the Muscular Dystrophies.” Three key sections for FSHD research are: Mechanisms Section, Research Objective 3, “Define the molecular pathogenetic mechanisms that lead to facioscapulohumeral muscular dystrophy”; Mechanisms Section, Research Objective 4, “Establish mouse (and cellular) models for facioscapulohumeral muscular dystrophy, specific to emerging candidate genes and/or disease genomics, to understand the epigenetic mechanisms and for the development of novel intervention strategies”; and, the Infrastructure Section, Research Objective 13, “Stimulate international collaborations and infrastructure sharing to ensure that opportunities are exploited and resources are used to maximum advantage, particularly in cases of novel opportunity or for the rare and/or understudied muscular dystrophies.” The full description and text of research objective three in the mechanisms section illustrates that the NIH fully comprehends what needs to be done to achieve progress in FSHD[1].

It is absolutely clear that muscular dystrophy is a high priority for the NIH and it understands the research that needs be developed, funded and contracted. However, the dystrophies such as FSHD with complex etiology, low prevalence or that present unique scientific opportunity are getting far less funding than they deserve. FSHD is clearly deficient in projects and funding caused by it being a complicated disease with complex etiology that requires mastery to review grants or to undertake research. In the dystrophy area, the NIH believes that insight gained from studying a specific type of dystrophy will provide benefit for all of the muscular dystrophies. Sadly, that is not the case for FSHD.

NIH Efforts on FSH Muscular Dystrophy (2000-Present)

NIH has supported several initiatives in recent years in dystrophy research and training. In response to the fiscal year 2000 report language, the NINDS, NIAMS and the NIH Office of Rare Diseases (ORD) held a research symposium in May 2000, in Bethesda, on the cause and treatment of FSH muscular dystrophy. The international team of researchers and NIH staff assembled research recommendations and directions that called for enhancing the understanding of the mechanism and molecular process associated with FSHD, strategies for exploring potential treatments and therapies, strategies to promote establishment of biomaterials registries and longitudinal and population based studies of FSHD, and a listing of required infrastructure and research resources.

The findings of the conference on FSHD were used to create NIH solicitations. One request focused on exploratory and high risk research applications on FSH muscular dystrophy, and several other announcements were made for grant applications on therapeutic and pathogenic approaches for muscular dystrophy in which FSHD was mentioned.

In September 2000, the NINDS and NIAMS issued a contract to establish and fund a National Registry for Myotonic and FSH Muscular Dystrophy based at the University of Rochester. Patients join the registry voluntarily by providing medical and family history data. The registry brings together FSHD patients and families seeking to participate in research with researchers seeking patients for research on the disorder.

Several program announcements were issued to promote large scale clinical and translational research in muscular dystrophy, as called for in the MD-CARE Act, called the Senator Paul D. Wellstone Muscular Dystrophy Research Centers. One of these centers, at the University of Rochester, focuses on myotonic and FSH muscular dystrophy. One quarter of this Wellstone MD CRC center focuses on the molecular pathology of FSHD and serves as a resource for cell lines, tissue biopsies, antibodies and data about gene expression. This Wellstone MD CRC core at Rochester is the only funding specific for FSHD in the six Wellstone MD CRCs.

The MD-CARE Act provides that the Wellstone MD CRC centers are not to replace funding and projects in existing basic research portfolios. In addition to building national infrastructure for dystrophy research, the NIH is expanding research resources for FSHD by funding several basic research grants related to understanding the mechanism and pathology of FSH muscular dystrophy.

One of these grantees, Rossella Tupler, supported by the FSH Society, helped bring about a momentous breakthrough in FSHD research. The prestigious scientific journal Nature made an advance online publication of “Facioscapulohumeral muscular dystrophy in mice over-expressing FRG1”, by Davide Gabellini and Rossella Tupler, et al., on December 11, 2005. The Nature paper is a breakthrough on multiple levels, it: 1.) creates an animal model for FSHD; 2.) points to a gene, called FRG1, that causes FSHD; 3.) identifies other genetic processes impacted by FRG1 over-expression involved in other major adult dystrophies; 4.) shows that both the FRG1 gene and mis-expressed pre-mRNA intermediary products can be targeted and regulated by new and novel gene therapy techniques to correct expression levels; and 5.) gives FSHD the hard target needed in order have better success in securing major funding from large agencies. They have demonstrated that transcriptional modulation of a gene from the region can produce an interesting, potentially relevant phenotype. This model can now be used to create conditional variants and ultimately move on to look for transcriptional suppressors of the phenotype.

The NINDS, NIAMS and NICHD support career development and training awards for muscle biology and neuroscience through three program announcements for domestic and foreign investigators to help create a cadre of new scientists and researchers working on muscular dystrophy. The NINDS, NIAMS program officers in dystrophy are working diligently trying to help extramural researchers submit the highest quality applications.

The NIH assisted Dr. Melanie Ehrlich of Tulane University, who was displaced by hurricane Katrina by offering a position in the NIAMS intramural research laboratory of Dr. Kuan Wang and granting supplemental relief funds to salvage her FSHD research.

NIH Muscular Dystrophy Funding

However, in the six years since the MD CARE Act was signed the NIH [NIAMS, NINDS, NICHD, NHGRI] funding for FSHD remains very small. Since 2000, the overall NIH wide muscular dystrophy budget has increased from $12.6M to $39.0M in FY2007 estimated. Since 2000, the FSHD budget has increased from $400,000 to $2.1M in FY2007 estimated. In the past year, at least five basic research grant applications (R01s) were submitted on FSHD and none were chosen for funding! Though the international field of FSHD researcher is small, the researchers are absolutely top-rate, world class and certainly competitive with other NIH grant applicants. Five applications represents about 25-30 percent of the entire field of FSHD researchers with the standing and experience to submit a basic research grant. A significant amount of FSHD researchers are submitting grant applications!

National Institutes of Health (NIH) Appropriations History

Source: NIH/OD Budget Office & NIH OCPL (Dollars in millions)

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

Year Dollars Dollars of NIH Dollars of MD of NIH

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

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

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

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

2004 $27,887 $38.7 0.139% $2.2 5.67% 0.0079%

2005 $28,494 $39.5 0.139% $2.0 5.06% 0.0070%

2006 $28,428 $39.3E 0.138% $2.1E 5.31% 0.0074%

2007E $28,428 $39.0E 0.137% $2.1E 5.38% 0.0074%

NIAMS has one research contract for FSHD, the National Registry for Myotonic and FSH muscular dystrophy for $295,888 (FY05). Its total muscular dystrophy portfolio for fiscal year 2005 was 57 projects, including two Wellstone MD CRC components for a total of $17,136,343. FSHD was only 1.7 percent of NIAMS FY2005 muscular dystrophy funding.

NINDS reports three research grants, one intramural grant, one research contract, and one-quarter of a Wellstone CRC for FSHD for a total of $1,359,930 in FY2005. The total muscular dystrophy FY2005 portfolio reported for fiscal year 2005 was 33 projects, including two Wellstone CRCs for a total of $11,987,219. FSHD was only 11.4 percent of NINDS FY2005 muscular dystrophy funding.

NICHD reports that approximately ten percent of its $4,762,321 fiscal year muscular dystrophy portfolio has some broad or general application to FSHD, but does not identify specific projects. The NICHD reports that $400,000 was spent on FSHD. The total muscular dystrophy FY2005 portfolio reported was 17 projects, including three Wellstone MD CRC components for a total of $4,762,321. FSHD was only 8.4 percent of NICHD fiscal year 2005 dystrophy funding.

The NIAMS, NINDS, NICHD, and NHGRI -- the four lead institutes on muscular dystrophy -- reported a combined total of 108 projects on muscular dystrophy totaling $34,285,883 in FY2005. Of that total amount facioscapulohumeral muscular dystrophy (FSHD) received $1,440,555 in directly titled funds for three grants, one contract and one-quarter of a Wellstone MD CRC.

The NIH now has six Wellstone MD CRCs, which are approximately equivalent to 27 basic research grants (R01). One-quarter of one Wellstone, or one R01 equivalent, has direct relevance to FSHD. Only 3.7 percent of the total Wellstone MD CRC expenditure is being spent on the second most prevalent adult muscular dystrophy or the third most prevalent form of muscular dystrophy affecting men, women and children.

Request

Mr. Chairman and Members of the Committee, we request an appropriation of $10M-12.5M to accomplish the FSH muscular dystrophy research plan as outlined by the NIH and submitted to the Congress. As a start, simply examining the scope of the work outlined in the NIH Action Plan for Muscular Dystrophy “Mechanisms Section, Research Objective 3: Define the molecular pathogenetic mechanisms that lead to FSH muscular dystrophy,” illustrates a requirement of at least 12 to 15 basic research grants (R01s) and/or high risk innovative research grants (R21s) that require $5M-6M to adequately fund them.

We also request that the umbrella area of muscular dystrophy receive an appropriation commensurate with similar disease areas, and we request equity by starting with a doubling of the current $39M to $80M to adequately fund the NIH research plan for dystrophy. NIH Disease Funding, Special Areas of Interest table shows that similar umbrella areas of health burden, scope, and impact such as Multiple Sclerosis ($109M), Motor Neuron Disease ($57M), Cystic Fibrosis ($89M), Parkinson’s ($223M), and Huntington’s ($48M) receiving average funding levels of $105 million. Muscular dystrophy affects hundreds of thousands of individuals, including family and friends.

We understand that the NIH overall budget went down in FY2006 to $28,428M from $28,494M and that Congress is strapped with other priorities. Chairman Specter, thank you for the constant and consistent support of biomedical research and for the NIH programs that offer hope for millions of sick and dying people. Mr. Chairman, members of the committee and members of Congress, the opportunities for FSHD research are greater than ever. The past year brought with it several major breakthroughs and discoveries and we are on the cusp of understanding FSHD and a never before seen class of disease. Now that we have a very refined plan of attack and research direction by the NIH, the need for funding is even greater. FSHD research needs to continue unabated and we remind you that there is no treatment or therapy for this devastating and crippling disease.

We ask the Subcommittee to appropriate in fiscal year 2007 $12.5M for FSH Muscular Dystrophy and $80M for Muscular Dystrophy either as new money towards the overall NIH budget or as a requested allocation/re-allocation of resources internally within the NIH, to support the NIH stated plan of action to work on dystrophy. We thank the Subcommittee for this opportunity to present our views.

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[1] NIH Action Plan for the Muscular Dystrophies, Mechanisms Section, Research Objective 3: “Define the molecular pathogenetic mechanisms that lead to facioscapulohumeral muscular dystrophy,” December 2005.

“Defining the molecular mechanisms by which a reduction in repeats at the D4Z4 translates into the multi-system symptoms seen in facioscapulohumeral muscular dystrophy has been difficult. Elucidation of the function of the allelic variants (A and B) at D4Z4 may help advance understanding of disease mechanisms. If perturbations of chromatin structure and/or derepression of gene expression ultimately figure into pathogenesis, there are some other diseases that could help inform researchers in this field. A potentially important avenue of research is the analysis of the chromatin structure at the D4Z4 locus, including methylation and/or binding of specific repressors or activators. Such chromatin conformational changes have been suggested as a possible disease mechanism, presumably affecting the regulation of expression of other genes. Since the issue of altered regulation of genes in the vicinity of D4Z4 remains controversial, there is a need for careful studies using microarrays or other techniques, to determine if genes near the D4Z4 repeat units on chromosome 4q, or at more distant locations on this chromosome, are up-regulated or down-regulated in facioscapulohumeral muscular dystrophy. The expression and function of the D4Z4 gene, DUX4, should be analyzed. The association of 4qter with the nuclear lamina and the potential role of this association upon gene expression profiles should be explored. Genetic causes for facioscapulohumeral muscular dystrophy, other than the D4Z4 contraction (such as non-chromosome 4 linked cases), should be investigated in available patients.”