A Publication of the Facioscapulohumeral Muscular Dystrophy Society SUMMER 2011 RESEARCH ISSUE FSH Watch 2011 CONNECTING THE COMMUNITY OF PATIENTS, FAMILIES, CLINICIANS AND INVESTIGATORS TRANSLATIONAL RESEArcH Journey toward developing a drug for FSHD Perspectives and updates from recently funded FSH Society grantees by DARKO BOSNAKOVSKI, D.V.M., Ph.D. University Goce Delcev Stip, Macedonia lthough FSHD is considered one Aof the most common inherited neuromuscular diseases, there is no Dr. Davide Gabellini with fellow researchers at the 2010 FSH Society FSHD research workshop specific therapeutic practice for it. So what can we do about it? First, we have TRANSLATIONAL RESEArcH to understand the mechanisms of the disease and to identify the crucial links in the chain of molecular reactions A possible approach for treating FSHD that underline FSHD. Furthermore, we have to develop a system to screen with RNAi therapeutics various therapeutic approaches, and in Perspectives and updates from FSH Society grantees the end to generate an animal model where clinical relevance of therapy by DANIEL PEREZ scientists: the Harper Lab at The Ohio State can be determined. When I joined the FSH Society University and Nationwide Children’s Hos- FSHD group lead by Dr. Michael Kyba with contributions by DAVIDE GABELLINI, Ph.D. pital in Columbus, Ohio, with a collabo- at University of Texas Southwestern six Division of Regenerative Medicine, San Raffaele rator in Modena, Italy; and the Gabellini years ago to develop a specific therapy Scientific Institute, Milan, Italy, and and Chamberlain labs in Milan, Italy, and for FSHD all of the above was considered Seattle, Washington, respectively. SCOTT Q. HARPER, Ph.D. to be a big enigma. We started working Center for Gene Therapy, The Research Institute at RNA interference is a natural cellular with DUX41, the gene within D4Z4, due Nationwide Children’s Hospital, Columbus, Ohio process that controls the levels at which to the similarity of its homeodomains certain genes are expressed. In this sense, it to those of the master myogenic genes wo exciting papers were recently pub- operates less like an on/off switch and more Pax3 and Pax72. We postulated that both Tlished on possible approaches for treat- like a molecular volume control knob. genes compete for the same target DNA ing FSHD using a disease gene silencing Over the last several years, many scientists sequences and with that the function of approach called RNA interference (RNAi). have been working to co-opt these natural myogenic cells is impaired. At that time The details emerged within one month gene-silencing strategies for therapeutic only a small portion of the scientific of each other in the journal Molecular purposes. Indeed, the main triggers of community, led by Alexandra Belayew Therapy. The two complementary stud- RNAi in the cell, called inhibitory RNAs or . continued on page 27 ies were performed by different teams of microRNAs, can be rationally designed in the lab to knock down disease genes. In the WHAt’s inside two molecular therapy studies, the research teams rationally engineered FRG1-targeted page page page page inhibitory RNAs and then delivered them 4 10 16 24 (-high) In Memory of Understanding the FSHD Society NIH BBRI Wellstone to muscles of dystrophic FRG1 mice Edward Schechter function of the DUX4 Grants recently MD CRC for FSHD using adeno-associated viral (AAV) vectors, gene in FSHD awarded accomplishments . continued on page 8 F rom T H E F SH Soc I E T Y P R ESIDENT & C E O Dear Friends, his issue of the FSH Watch reports great advances and Please consider participating in Board of Directors Tdedicated people making remarkable progress to- studies highlighted in this issue, Daniel P. Perez, President & CEO ward understanding and treating FSHD. We are proud including the natural history William R. Lewis Sr., M.D., of the work detailed in this issue, moving us closer to study and developing biomark- Chairman Howard Chabner, J.D., understanding and treating FSHD. The FSH Society has ers for FSHD. Vice-Chairman made excellent progress in bringing scientists into the The FSH Society’s research Carol A. Perez, M.Ed., field, allowing them to train, and in giving them oppor- portfolio seeks a good balance Secretary William Michael, C.P.A., tunities to develop ideas in FSHD. We hope you agree. between conservative and in- Treasurer In last year’s research issue we highlighted Society novative approaches in devel- E. Ann Biggs-Williams Robert H. Brown Jr., M.D./ seed-funded work by Drs. Lemmers et al. in their paper oping our knowledge of how Daniel Paul Perez D.Phil.* “A Unifying Genetic Model for Facioscapulohumeral FSHD works. We are constantly James A. Chin Sr. President & CEO JoAnn P. Forance Muscular Dystrophy,” Science, August 19, 2010, that put readjusting between following David J. Glass, M.D. forth a unified and long-sought explanation of the exact the “published paradigm” to William S. Herzberg Beth E. Johnston, M.B.A. biological workings of a disease that affects an esti- guide FSHD progress with that of setting out in new Louis M. Kunkel, Ph.D. mated one in 14,000 or 22,100 Americans and 490,000 innovative directions to improve our understanding C. Larry Laurello, P.E. William R. Lewis III, M.D. individuals worldwide. Subsequently the Society an- of the disease. Both attitudes are appropriate. In times Michelle H. Mackay, M.A. nounced that it helped to fund a second critical advance like these, when the research community struggles with Theodore L. Munsat, M.D.* Paul Schultz, M.D.* in determining the cause of FSHD in PLoS Genetics, developing a high-confidence therapeutic target, a bias Judith Seslowe, M.A. “Facioscapulohumeral Dystrophy: Incomplete Suppres- towards innovation is appropriate. Robert F. Smith, Esq. Christopher Stenmon, C.P.A. sion of a Retrotransposed Gene,” on October 28, 2010, A top priority as outlined by the international com- Scientific Advisory Board that shows that the disease is caused by the inefficient munity during the most recent Society research planning David E. Housman, Ph.D., suppression of a DUX4 gene that is normally expressed workshop is to independently verify and confirm the Chairman only in early development. DUX4 hypothesis as published in Science in 2010. And if Michael R. Altherr, Ph.D. Robert H. Brown Jr., M.D./ The FSH Society’s approach to solving FSHD is confirmed, move to understand normal DUX4 function, D.Phil. pragmatic. We are now studying the “FSHD causing and finally, move towards understanding the naturally Rune R. Frants, Ph.D. David J. Glass, M.D. targets” in our translational research phase to enable us occurring variability of DUX4 to allow scientists to Louis M. Kunkel, Ph.D. to initiate therapeutic clinical trials. In this issue, we manipulate the disease in our favor. Currently, the pub- William R. Lewis Sr., M.D. William R. Lewis III, M.D. highlight efforts in each of the areas supported by the lished paradigm is that DUX4 is necessary and sufficient Katherine D. Mathews, M.D. Society – mechanistic, translational, pre-clinical and to cause FSHD. However, if it turns out that DUX4 is Theodore L. Munsat, M.D.* George W. Padberg, M.D. clinical. The FSH Society continues to fund ground necessary but not sufficient or even not necessary to Paul Schultz, M.D.* breaking and early-stage efforts in research, translational cause FSHD, then the choices of a target and pathway Kathryn Wagner, M.D., Ph.D. research, small molecule screening and clinical efforts. are markedly different. It is one thing to eliminate a pro- General Counsel Morgan Downey, J.D. As you read about the projects we’ve recently funded tein that you are not supposed to have at all in muscle Washington, DC and the updates from scientists all over the world, please and another to modulate a protein that has a resolution * Board Member Emeritus remember that great things are happening, and they near the noise floor of detection and may be expressed are only made possible by your financial donations and at different thresholds in individuals with FSHD and FSH Watch willingness to actively participate in research efforts. without FSHD. SUMMER 2011 It is our editorial policy to report on developments regarding FacioScapuloHumeral Muscular Dystrophy (FSHD), but not to endorse any of the drugs or treatments discussed. We urge you to consult with your own physician about the procedures mentioned. Nancy Van Zant Executive Director [email protected] The FSH Watch is published by the FSH Society and distributed by mail to its members and supporters. All material is copyrighted and may not be reproduced without written permission. To be placed on the mailing list or to submit an article, please write to: Daniel Paul Perez Research Programs Nancy Van Zant, Executive Director [email protected] FSH Society, Inc. Patient Resource c/o BBRI R353, 64 Grove Street, Watertown, MA 02472 USA Peer-to-Peer Team [email protected] Call or email the Society office to make contact Articles may be edited for space and clarity. Every effort has been made to ensure accuracy in the newsletter. If you wish to correct an error, please write to the above address. FSH Society, Inc. 64 Grove Street Look for us on the internet at: www.fshsociety.org Watertown, MA 02472 USA 617-658-7878, -7877 Editors: Daniel Paul Perez and Nancy Van Zant. 617-658-7879 Fax Editorial assistance: Howard Chabner, Carol Perez, Susan Perez and Charles Perez. Graphic design & editorial assistance: Leslie Anne Feagley www.fshsociety.org 2 • FSH Watch • SUMMER 2011 Two papers on possible approaches for treating FSHD using established for other dystrophies.