FSH Society research and fellowship grant awards provide vital startup funding for investigators in FSHD and research projects on FSHD. The fellowship program allows innovative and entrepreneurial research to develop and ultimately attract funding from large funding sources such as the US National Institutes of Health (NIH). Without the FSH Society research and fellowships program, many key initiatives in FSHD research might never have had the chance to begin. Well over 300 peer-reviewed papers have been published by FSH Society-funded researchers.
The FSH Society convenes an annual International Research Consortium Planning meeting to review progress towards scientific goals and set research priorities for the coming year.
2017 Research Priorities
General areas of interest include — tissue, cell and molecular biology studies of FSHD, the development of animal models for FSHD, biomarkers and outcomes measurements and clinical trials readiness. Proposals are sought for research that helps with understanding of the genetic, pathophysiological, neuromuscular and developmental mechanisms of the disease. Further, there is interest in the development of cell, small-molecule and gene therapy, genomic engineering technologies and other therapeutic programs that may arise from that understanding.
Specific areas of interest as highlighted in the FSH Society’s 2016 annual research consortium include — Molecular mechanisms (understanding genetic toxicity in FSHD; Understanding Dux4 and how to silence it. How to silence the RNA; understanding what real pathophysiology is in FSHD; studying relationship to other markers and correlation between the expression and activity, transcriptional activity of DUX4). Genetics and epigenetic (studies that focus on the uniformity in the genetic testing and the subgrouping of patients as so far as that is possible; understanding of the epigenetic regulation of the repeats helps us to better understand the disease process and the disease mechanism; Modifiers of the disease mechanism). Clinical studies (surrogate outcome biomarkers, validated outcome measures; natural history studies; studies to identify, validate, and determine the best standard measurements are critical for trial preparedness in FSHD). Models (research that helps focus to ensure that we are measuring the same kinds of things, that it does translate into a usable tool for our therapeutic industry; development, characterization and use of animal models – whole animal; mice; fish; pig and mammal; emphasis on cellular models; research on models to help develop precisely how you deliver, how you formulate, how you get the conceptual entity to the effective therapeutic use of the entity requires something that you can test).
Please click on the links or drawers below to read previous research priorities documents.
Research Priorities for 2015
II. Mechanisms and targets. The discussion focused on the mechanism of DUX4 expression (bursts), including up-and downstream steps. Although there is much evidence for stochastic expression bursts of various genes, (muscle-specific) factors may specifically facilitate bursts of DUX4 in adult muscle – normally expressed only in embryonic tissue. The significance of DUX4-inducedlink with apoptosis is not understood, though it has been shown that the RNA (and protein) spreads to multiple nuclei in the same fiber. Why FSHD preferentially affects skeletal muscle, whether reflecting the DUX4 expression or toxicity, is particularly toxic in muscle is poorly understood and in need of further work as it might reveal interesting intervention targets.
III. Models. During the past several years, various models have been generated, most of them focusing on DUX4. In the past year, the most intriguing ones are:
- The long-awaited inducible mouse model. No muscle phenotype was detected before these juvenile animals die. However, a defect in regeneration was demonstrated when muscle stem cells from these animals were transplanted. This model may be useful for testing in vivo activity of anti-DUX4 therapeutics.
- Various virus viral delivery-based models have been reported. Depending on amongst other the delivery system, these models can produce burst-like expression patterns of small numbers of myonuclei expressing DUX4.
- Two labs reported on the generation of stem cells, embryonic and induced ones. Although in an early stage, this approach might prove very interesting also for fundamental studies on DUX4 and chromatin structure.
IV. Patients – trial preparedness. For FSHD phenocopies (non-D4Z4 or SMCHD1 mutated) all agreed that differential diagnosis has to be ruled out (by muscle biopsy and genetics) and it was advised to put these cases in an international repository. On trial readiness the audience suggested to reach for a worldwide agreement on a severity score and a standpoint on the FSH-com and a patient reported outcome in order to be able to compare clinical trials more easily. Other suggestions that were briefly discussed:
- To study which methylation assay would separate best patients from controls.
- The need for more groups to study biomarkers in order to select the best ones for follow-up of patients.
- More studies on Electrical Impedence Myography (EIM) are needed to find the shortest time interval to demonstrate significant changes in muscles.
- Integration of MRI in the clinical discussions of FSHD.
Background These priorities were developed at the 2014 FSHD International Research Consortium and Research Planning meetings. Close to 80 scientists, patients, advocates, biotech and pharmaceutical companies, and clinicians from throughout the world gathered at a satellite meeting of the Annual Meeting of the American Society of Human Genetics in San Diego on October 17-18, 2014, sharing their latest progress in facioscapulohumeral muscular dystrophy (FSHD) research at the 2014 FSHD International Research Consortium and Research Planning meetings. The Meeting was chaired by Dr. Michael Altherr (Los Alamos National Laboratory, Los Alamos, New Mexico), Dr. Stephen Tapscott (Fred Hutchinson Cancer Research Center, Seattle, Washington) and Dr. Silvère van der Maarel (Leiden University Medical Center, Leiden, the Netherlands and co-PI of the Fields Center for FSHD and Neuromuscular Research). David Housman, MIT, Cambridge, Massachusetts and Daniel Perez, President & CEO of the FSH Society, Lexington, Massachusetts served as the organizational chairs.
The goal of this meeting was to integrate clinical and basic FSHD research, explore and verify the complex disease mechanism and various features of FSHD, and to follow up on considerations to move into the development of potential treatments for FSHD. Other research directors attending the meeting were Greg Block of PNW Friends FSH, Seattle, Washington, Mr. Kees van der Graaf represented the Dutch FSHD Foundation and FSHD Europe, Mr. Patrick Cameron of FSHD Global Research of Australia, Mr. Neil Carmata of FSHD Canada, Mr. Christopher Carrino and Mr. Chris Hughes of the Chris Carrino Foundation for FSHD, and Andrew Graham, MD Campaign, UK. All volunteer agencies working on FSHD were invited by the organizers and encouraged to attend. The FSH Society was represented by Dr. Michael Altherr, Mrs. June Kinoshita and Mr. Bill Lewis, Sr., Dr. Louis Kunkel, Dr. Rune Frants and Dr. George Padberg. Sponsors for the research workshop included: aTyr Pharma, Association Française Contre les Myopathies (AFM), Cytokinetics, FSHD Canada, FSH Society, FSHD Global Research Foundation, Genzyme, a Sanofi Company, Muscular Dystrophy Association United States (MDAUSA), and NIH Eunice Kennedy Shriver NICHD Senator Paul D. Wellstone MDCRC for FSHD at University of Massachusetts Medical School.
After a brief welcome by the organizers including an overview of last years’ priorities and the follow up on these priorities by the FSHD community in 2013. There was a general consensus that, based on the publications that have appeared in the past year, there had been an impressive response to the priorities formulated during the 2013 meeting. The overview was followed by a series platform sessions reviewing the latest advancements in (1) clinical studies, (2) genetics and epigenetics, (3) molecular mechanisms, (4) models, and (5) therapeutic studies. Each platform session included presentations from several speakers selected from the pre-submitted abstracts. Sufficient time was allowed after each of platform sessions each moderated by two distinguished scientists whose role was to provide a stimulating overview of the topic and facilitate discussion. During the breaks there was ample time to review and further discuss the latest developments at the posters. The meeting was a working meeting with experts, developing future plans in the context of what we know now. It was a very successful workshop with a positive, constructive and collaborative atmosphere where new and unpublished findings were communicated to the audience, and with excellent interaction between all participants.
The second day was solely dedicated to the Discussion and Planning Session, included several sessions chaired and moderated by Drs. Altherr, Frants, Tapscott, Van der Maarel, and Padberg. From these discussions the following conclusions were made and priorities were defined.
Research Priorities for 2014
Brief Summary of Priorities and General Discussion, Tuesday October 22, 2013
DUX4. The unanimous conclusion of the general discussion was that overexpression of the toxic transcription factor Dux4 is at the root of FSHD1 and FSHD2. Expression of flDUX4 mRNA (and protein) is dependent on two conditions: 1. A specific DUX4 haplotype containing a poly-A site and 2. An open chromatin structure, due to D4Z4 repeat contraction-dependent (FSHD1) or contraction-independent (FSHD2) mechanisms, the latter due to mutations in the SMCHD1 gene encoding a chromatin modulating enzyme. There are indications for further genetic heterogeneity, thus additional gene defects causing FSHD. The chromatin relaxation of the DUX4 region (close to the #4q telomere) can induce additional gene expression effects in cis (#4) and trans (other chromosomes). As Dux4 is a transcription factor, the over-expression can trigger a cascade of downstream molecular pathways contributing to the large variability in the clinical phenotype and natural history of FSHD. Conclusion: DUX4 expression is necessary but not always sufficient to cause FSHD. Research should focus on upstream and downstream molecular pathways and mechanisms as they form the most plausible intervention targets.
Disease models. The field needs improved and specific in vivo (animal) models for mechanistic and intervention studies. At this stage it is not sensible to give strict recommendations. Inducible (conditional) models seem necessary to dissect spatial and temporal effects of the DUX4 pathway. For specific questions, simpler models, like zebra fish may have unique potential. Various xenograph models aiming at generating human muscle in mouse muscle are promising, but strongly dependent on availability of human muscle biopsies or cell lines. In other muscle disease fields, AAV mediated “gene therapy” has proven its value. Availability of higher vertebrate models (e.g. dog, primates, etc.) may be helpful to study intervention effects prior to human trials.
Intervention. Is there a magic bullet for FSHD treatment? Although the DUX4 over expression is crucial, various biological and chemical (pharma) strategies can be envisaged to intervene with the overall expression mechanism, directly by targeting the mRNA or the protein, or indirectly by modulating the transcription machinery, including the chromatin structure. As the ultimate goal is to influence the clinical phenotype and disease progression, intervention in specific molecular subpathways of the DUX4 cascade may form alternative strategies.
Clinical studies and trial readiness. There is an urgent need for better understanding of the natural history of FSHD, for example, the clinical heterogeneity between and within families, the asymmetric expression of the disease, the cause and consequence of inflammation, and the effect of physical and cognitive training etc. The FSHD field is working hard to establish patient databases with detailed clinical and genetic information. Equally, the development of sensitive quantitative clinical monitoring methods to follow intervention trials has a high priority. It is important to closely follow the situation in related fields, for example, Duchenne, etc.
Priorities for 2014
- The DUX4 interactome
- Understanding DUX4 manifestation and variation
- Additional genetic heterogeneity; non-FSHD1 and 2
- Disease models
- Well documented Natural history with reliable endpoints; modulating mechanisms/genes
- Increasing data depth of patient databases with extensive (follow-up) clinical data
- Prepare for clinical trials: reliable and meaningful outcome measures; with access to discreet patient populations and disease mechanism of action classes.
- Therapy; proof-of-principle experiments
- Focus on translational research; from clinic to bench and back
- Understanding pathophysiology of FSHD: connection to DUX4, heterogeneity, asymmetry, role of inflammation; infiltrates and etiology
2013 Request for Proposals: Employing Genomic Engineering Techniques for Modification of DUX4
Current theory indicates that the majority of FSHD cases results from a genomic contraction of a DUX4-containing DNA repeat near the terminus of the long arm of chromosome 4. Furthermore, this contraction provides a transcriptionally permissive chromatin environment, which coupled with a DNA polymorphism that produces a functional polyadenylation site immediately adjacent to the final copy, allows and creates a stable DUX4 transcript that produces a protein with potent deleterious properties. The impact of an exceedingly small amount of a molecule like DUX4 to initiate such a devastating pathological cascade is going to be a significant therapeutic challenge likely requiring a multi-pronged approach to ameliorate the consequences of the disease cascade. However, the association of a small highly specific DNA polymorphism that leads to a distinct phenotype (in this case, FSHD disease) is reminiscent of a classic dominant gain-of-function mutant. Moreover, if theory is correct, the specific disruption of the site that gives rise to the polyadenylation signal should prevent the translation of the DUX4 protein and eliminate it as the trigger of the pathological cascade that gives rise to FSHD. Recently, a number of techniques have emerged that allow the targeted “engineering” of specific sites in the genome (e.g., TALEN and CRISPR).
The FSH Society would be interested in seeing proposals using genomic engineering techniques that specifically target the DUX4 gene and include an assessment on the impact of these types of DUX4 manipulations on one or more phenotypic measures.
Mechanism of Support: Up to $125,000 in funding is available for one year. Smaller and larger budgets will be considered if accompanied by adequate justification. Applications may be submitted by non-profit academic institutions and for-profit organizations, worldwide.
The deadline date for our current grant review cycle is August 31, 2013. Submission of a Letter of Intent (LOI) is required prior to August 15, 2013, sent to firstname.lastname@example.org.
The full Application form can be downloaded here: http://www.fshsociety.org/assets/pdf/FSHGrantAoplication2012.pdf
2013 The FSH Society Invites Grant Applications for Research on Facioscapulohumeral Muscular Dystrophy (FSHD)
Evidence continues to accumulate suggesting that the ectopic expression of DUX4 is a trigger leading to a pathologic cascade culminating in FSHD disease. Current theory indicates that the majority of FSHD cases results from a hypomethylation-associated chromatin relaxation of DUX4-containing DNA repeats near the terminus of the long arm of chromosome 4. The more common form, FSHD1, is caused by a genomic contraction of the D4Z4 repeat array, while FSHD2 is caused by a contraction-independent hypomethylation. These genomic modulations provide a transcriptionally permissive chromatin environment that coupled with a DNA polymorphism produces a functional polyadenylation site immediately adjacent to the final copy and creates a stable DUX4 transcript that produces a protein hypothesized to have potent deleterious properties.
The FSH Society is especially interested in research proposals aimed at elucidating the pathogenic cascade that results in muscle destruction in FSHD. High priority will be given to applications that are suitably powered, involve cross-sector or interdisciplinary collaborations, or explore truly novel ideas. Priority Areas for the Request for Proposals include:
- Understanding the pathophysiology of FSHD muscle degeneration, from early onset to loss of function.
- Robust model systems of disease pathogenesis.
- Identification of disease-modifying genes in FSHD.
- Identification of events that trigger the onset of FSHD muscle degeneration.
Access to FSHD samples: The FSH Society can facilitate access to patient specimens, including blood and primary muscle tissue collected from 42 family cohorts with over 100 individuals, situated at the Senator Paul Wellstone Centers for FSHD Research.
Mechanism of Support: Up to $125,000 in funding is available for up to two years. Smaller and larger budgets will be considered if accompanied by adequate justification.
Applications may be submitted by non-profit academic institutions and for-profit organizations, worldwide. The deadline date for applications is August 31, 2013.
Research Priorities for 2013 and Beyond
Priorities as Stated by FSHD Research Community for FSHD Research: 2013 and Beyond at the International Research Consortium meeting in November 2012
The summary and recommendations of the group state that given the recent developments in our definition of FSHD1A and FSHD1B [FSHD2] and there is a need to ramp up the preclinical enterprise and build/organize infrastructure needed to conduct clinical trials on FSHD1A and FSHD1B. Our immediate priorities should be to confirm the DUX4-fl hypothesis, if valid then understand normal DUX4 function, and finally, understanding the naturally occurring variability should allow us to manipulate the disease in our favor. We need to be prepared for this new era in the science of FSHD, by accelerating efforts in the following five areas:
1. Genetics/epigenetics. There is general acceptance that transcriptional deregulation of D4Z4 is central to FSHD1 and FSHD2. The FSHD2 gene SMCHD1 explains approximately 80% of FSHD2. There is a need for better understanding of the factors that modulate DUX4 activity and disease penetrance.
2. FSHD molecular networks. D4Z4 chromatin relaxation on FSHD-permissive chromosome-4 haplotypes leads to activation of downstream molecular networks. In addition to considering DUX4 as the “target” and downstream targets, the upstream processes and targets—triggering of activation—are equally important. Hence, understanding what DUX4lf does as a target and targets up- and down-stream of it are priorities. Detailed studies on these processes are crucial for insight in the molecular mechanisms of FSHD pathogenesis and may contribute to explaining the large intra- and interfamily clinical variability. Importantly such work may lead to intervention (possibly also prevention) targets. Additional FSHD genes and modifiers are still likely to exist. Apart from chromatin modifiers, these include, but are not limited to, CAPN3 and the FAT1 gene that was recently suggested to be involved in FSHD.
3. Clinical trial readiness. It is now broadly accepted that deregulation of the expression of D4Z4 / DUX4 is at the heart of FSHD1 and FSHD2. This finding opens perspectives for intervention along different avenues. Intervention trials are envisaged within the next several years. The FSHD field needs to be prepared for this crucial step. There is an increasing need to improve the translational process. This includes, but is not limited to, the need for consensus on data capture and storage, overcoming national and international barriers, definition of natural history, identification of (meaningful) and sensitive outcome measures, biomarkers, and meaningful functional measures. There is a need to work more closely with FDA to help define acceptable measures for trials.
4. Model systems. There was already a good set of cellular and models, based on different pathogenic (candidate gene) hypotheses. This was further expanded during the last year. The phenotypes are very diverse and often difficult to compare with the human FSHD phenotype. Many basic questions remain unanswered and dearly need to be answered for further translational studies: when and where is DUX4 expressed in skeletal muscle and what regulates DUX4 activity. It was recognized that there still exists a gap in our knowledge linking the basic genetic and molecular findings with the observed muscle pathology. The BBRI NIH Sen. Wellstone center and the Fields Center continue to generate human cellular resources. These resources continuously deserve attention and need to be replenished. Recent progress in ES-cell technology, including iPS lines, allows for inter-group distribution and dedicated molecular (epi)genetic studies.
5. Sharing. Timely sharing of information and resources remains a critical contributor to the progress in the field. Wellstone and Fields Center continue to share their resources to the scientific community. The Fields Center website also continues to share other information (e.g. protocols, guide to FSHD muscle pathology, etc.). We thank you for your financial support of the FSH Society FSHD International Research Consortium Workshop to help foster significant progress in both collaboration on FSHD and our understanding and treating FSHD.
Research Priorities for 2012
Priorities as Stated by FSHD Research Community for FSHD Research: 2012 and Beyond
The international FSHD clinical and research community recently came together at the DHHS NIH NICHD Boston Biomedical Research Institute Senator Paul D. Wellstone MD CRC for FSHD. Almost 90 scientists working on FSHD globally met at the 2011 FSH Society FSHD International Research Consortium, held November 7-8, 2011.
The summary and recommendations of the group state that given the recent developments in our definition of FSHD and the potential that within one to two (1-2) years, evidence-based intervention strategies, therapeutics, and trials being planned and conducted. Our immediate priorities should be to confirm the DUX4 hypothesis, if valid then understand normal DUX4 function, and finally, understanding the naturally occurring variability should allow us to manipulate the disease in our favor. We need to be prepared for this new era in the science of FSHD, by accelerating efforts in the following four areas:
1. Genetics/epigenetics. It is now broadly accepted that disregulation of the expression of D4Z4 / DUX4 is at the heart of FSHD1 and FSHD2. Additional FSHD (modifier) loci are likely to exist. FSHD molecular networks. The relaxation of the chromatin structure on permissive #4 haplotypes leads to activation of downstream molecular networks. Importantly, the upstream processes—triggering of activation—are equally important. Detailed studies on these processes are crucial for insight in the molecular mechanisms of FSHD pathogenesis and may contribute to explaining the large intra- and interfamily clinical variability. Importantly such work may lead to intervention (possibly also prevention) targets. Additional FSHD genes. FSHD2 is characterized by hypomethylation of D4Z4 on #4 as well as #10. This also leads to bursts of DUX4 expression. Identification of the responsible factor (gene) and molecular mechanisms is of utmost importance. This work will be facilitated by the recruitment of additional families. Also other genes need to be considered that may give rise to FSHD-like phenotypes. These include, but are not limited to, CAPN3 and the FAT1 gene that was recently suggested to be involved in FSHD.
2. Clinical trial readiness. It is now broadly accepted that disregulation of the expression of D4Z4 / DUX4 is at the heart of FSHD1 and FSHD2. This finding opens perspectives for intervention along different avenues. Clinical Trial Readiness. Intervention trials are envisaged within the next several years. The FSHD field needs to be prepared for this crucial step. To design and coordinate this important translational process, it was envisaged to install an international task force Clinical Trial Readiness (FSHD-CTR), with Dr Rabi Tawil as leader. The FSHD-CTR needs to be a multidisciplinary group, including members with expertise, not only in FSHD but also, in trial design and execution, statistics, (non-invasive) biomarkers etc. Important issues are: Natural history Homogeneous clinical criteria Biobanks, biomarkers etc. Reliable outcome measures Patient registries Biomarkers. Sensitive biomarkers are needed to monitor intervention: they might also improve diagnosis. Important to consider biomarkers established from easily accessible sources like blood. Non-invasive methods like imaging needs further attention. Quantitative muscle function methods are instrumental as are patient-reported indicators.
3. Model systems. There are a plethora of cellular and models, based on different pathogenic (candidate gene) hypotheses. Moreover, the phenotypes are very diverse and often difficult to compare with the human FSHD phenotype. FSHD Model Data Base. The importance of a systematic database was recognized. This DB should contain detailed information on the molecular characteristics of the model (design and phenotype). Particular emphasis should be paid to the muscle pathology. Non-muscle phenotypes – described also in FSHD patients deserves attention. Human pathology and bio-banking. Importantly, this DB should also contain well-documented muscle pathology data of patients – astonishingly difficult to find in the literature. Human cellular resources continuously deserve attention. Recent progress in ES-cell technology, including iPS lines, allows for inter-group distribution and dedicated molecular (epi)genetic studies.
4. Sharing. Timely sharing of information and resources remains a critical contributor to the progress in the field. There are several initiatives that create large repositories of data and resources, e.g. Wellstone and Fields Center. Their websites should be used for sharing of information (e.g. protocols, guide to FSHD muscle pathology (images), model systems, contact information), reagents, and resources.