FSH Society Tactical and Strategic Research Plan

 

FSH Society Research Plan to Solve FSHD

On October 21-22, 2010, scientists, patients, advocates, biotech and pharmaceutical companies, and clinicians from throughout the world gathered to attend the FSH Society 2010 International Research Consortium and Research Planning Meetings for facioscapulohumeral muscular dystrophy (FSHD). 

Over 90 researchers and clinicians from institutions, industry and funding agencies gathered from across the United States and around the world.  It was a very successful planning meeting and really was "the place to be" for FSHD research. The atmosphere was very positive and constructive and all in attendance felt that it was one of the most productive meetings to date.  Also was excellent to see that the interaction between the U.S. NIH BBRI Wellstone Muscular Dystrophy Cooperative Research Center for FSHD and Fields Center for FSHD are becoming stronger, evidenced by several announcements and agreements to work jointly and corroboratively on projects. Also, excellent to see most all FSHD organizations working extremely well together side by side in the common front to solve and treat FSHD.

Sponsors for the event included Association Française Contre les Myopathies (AFM), The Fields Center for FSHD and Neuromuscular Research, FSH Society, FSHD Global Research Foundation, NIH Eunice Kennedy Shriver NICHD Boston Biomedical Research Institute Senator Paul D. Wellstone MDCRC, and the Muscular Dystrophy Association United States (MDAUSA).

This 2010 workshop participants included clinicians, scientists, biotechnology companies, pharmaceutical companies, government and non‐profit funding agencies, and patients – committed to solving, treating and curing FSHD at this workshop.  Over the course of the two days the FSHD community presented the latest findings/data and had various breakout discussion groups and whole group discussions which culminated in discussions to identify areas in need of development and funding in FSHD.  During the Planning components of the meeting all attendees collectively developed a list of future plans in the context of what we know now. In the interest of time, we emphasized new data and ideas and to avoid restating data that has already been published.

The summary and recommendations of the group stated 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.  Click here to view the full IRC Workshop 2010 Working Consensus of Tactical and Strategic Research Priorities for FSHD. The group stated that we need to be prepared for this new era in the science of FSHD, by accelerating efforts in the following ten areas:

1.         Shareable Protocols.  There is a need for access to FSHD research protocols and experimental methods by FSHD researchers internationally.  Needed are available, clear and well defined research protocols to allow verification, standardization and corroboration of research findings and publications.

2.         Common and shareable materials and data by whole community.  There is a need for global and international biomaterials and data management.  Needed are schemas to identify source and context of biomaterials and data, meaningful data identifiers, and easily accessible bio-repositories and data sources.

3.         Corroborate and verify DUX4 finding.  This line of work will be instrumental to pinpoint the real identity of FSHD1A (chromosome-4-D4Z4-contraction-linked cases) and FSHD1B (chromosome-4-non-D4Z4-contraction-linked cases & non-chromosome-4-linked cases). This information will form the basis for evidence-based intervention.  There is a need to verify and reproduce the DUX4 finding using multiple sites and patient materials.

4.         FSHD alleles in context of population genetics need to be defined.   There is a need to understand the normal function of the short DUX4 transcript in every human being and the abnormal function of toxic long-form of the DUX4 transcript.

5.         Biomarkers. There is obvious need for monitoring intervention.  There is the need to define biomarkers for clinical trials endpoints, to understand the FSH disease at multiple omics levels and to understand pathways and signaling of FSHD through “omics” analysis

6.         FSHD clinical evaluation scales/systems need be defined under one agreed standard.  There is an important need to have a comprehensive and single clinical evaluation standard to allow a list of clinical identifiers and parameters to be assembled into a thorough and  robust dataset.  This can be applied to subsequent systems biology and –omics areas.

7.         Working Groups / Mouse model working group consortium.  There is a need for models and methods to interpret the current mechanistic paradigm of FSHD and fidelity of current data.  What is needed is an assessment of various modeling approaches.  Short and near-term we need consensus on the limits and capabilities of current modeling approaches. 

8.         Model systems for mechanistic, intervention work and advancement to clinical trials.  We need to be able to understand the limits of the both data and models.   There is the need to address the complexity of FSHD in the context of mammalian systems.  It becomes even more important to have a solid model and dataset to test.

9.         Epigenetics / Genetics.  There is the need to further evaluate FSHD1, FSHD2 and phenocopies using the genetic approach.  Resolve and establish genes involved in the pathophysiology of FSHD (DUX4, FRG1, FRG2 and other 4q35 loci, PitX1, Pax3, Pax7 and other impacted distributed loci, related cascades and pathways, etc.)

10.       Clinical trials readiness.  There is a need to revisit we know about the pathological progression

Click here to view the full IRC Workshop 2010 Working Consensus of Tactical and Strategic Research Priorities for FSHD

A Historical View of the First FSH Society International Consensus and Planning Meeting For FSHD

In 2006, in Cambridge, Massachusetts the FSH Society organized and sponsored a planning meeting of its Scientific Advisory Board (SAB) and other members of the FSHD research community, including scientists, clinicians, and representatives of funding agencies and the biotech industry. With input from the other participants, the SAB developed the FSH Society FSHD Tactical and Strategic Research Plan – a review of FSH Society grant funding, how it has been spent, and what it has accomplished; and an assessment of how to go forward to find treatments and a cure for FSHD.

In addition to FSH Society sponsorship, the meeting was generously sponsored by the Muscular Dystrophy Association USA (MDAUSA); FSH Society Board of Directors member William Herzberg, M.D., and his family; Genzyme Corporation; and the Association Française Contre les Myopathies (AFM).

Research team leaders were given the charge to present the major findings by their groups, not necessarily their most current data. Finally, the researchers were asked to identify their perception of the most important issues impacting FSHD research, both on their own research and on the field as a whole.

The presentations were kicked off with an outstanding overview of the phenotypic spectrum of the disease. This talk and many that followed began to identify a number of focal points that would facilitate further understanding of FSHD pathogenesis. Of particular note, the discussion on the marked asymmetry and different developmental lineages of the muscles involved sparked consideration of the parallels to the plethora of effects caused by developmental pattern regulatory genes. A recurring theme appeared in the next several talks that involved understanding the difference between normal and disease state, and the absence of a natural history of both normal and disease muscle at the molecular, cellular, physiological and histological levels. This is something that could be facilitated by a systems biology approach.

The subsequent presentation provided one of the most stimulating discussions of the day, focusing on two enormously interesting and related issues. One group has made significant progress in using ectopic expression of suspect coding sequences to produce a mouse model. Although not completely concordant with the disease phenotype (e.g. how do you evaluate facial weakness in the mouse?), there are a number of important parallels between the mouse model and human disease, and a number of observations suggest a potentially important role for FRG1 in the disease. Strikingly, a previously unappreciated facet of FRG1 mis-regulation was initially identified in the mouse construct, aberrant mRNA splicing. This phenomenon was subsequently confirmed in the processing of FSHD patients' RNA from derived cell lines. Similar mouse constructs using other coding segments from the suspect genomic segment failed to produce significant altered phenotypes. These findings appeared in conflict with those of another group, who apparently attempted to create similar constructs but without significant effect. Unfortunately, those studies, largely negative in their findings, have not been published. Nonetheless, the “availability” of the affected mouse drives an enormous amount of experimental interest.

While the discordant findings were initially disquieting, much of the later discussions focused on the epigenetic potential to modulate gene expression by nuclear localization and chromatin modifications associated with the contraction of D4Z4 repeats, leading one to believe that it might even be expected. For example, the choice of promoter or other aspects of the construct, the site of trans gene integration, or even the subsequent chromatin modifications of the trans gene could have profound impacts on the resultant phenotype. The quixotic nature of this disease and phenomena associated with it suggest to always expect the unexpected. The disparate mice results were not the only incongruities identified during the meeting, and the complexity of the problem screams out for well defined controls and reagents, and uniformity in experimental execution.

There was a consensus among the investigators on the need to establish a process to arbitrate experimental discrepancies leading to paradoxical findings through independent validation, third party, or double blind studies; and for the production, utilization and distribution of baseline reagents and detailed protocols in an effort to eliminate variability resulting from subtleties associated with experimental materials and techniques. While the Society’s research budget is modest compared to that of the NIH or MDAUSA, the Society could greatly facilitate the research endeavor by facilitating a centralized coordinating role.

The FSH Society research plan initial draft was prepared by SAB member Michael R. Altherr, Ph.D., of Los Alamos National Laboratory, after a meeting of the SAB following the larger meeting.

This plan and related recommendations will guide the direction of the FSH Society’s research programs, and will help optimize FSHD research funding by federal agencies, non-profits and private funding sources.

This website is, in part, a response to the recommendations of the plan.  Through this website and by other means, the FSH Society is working to foster uniformity and eliminate discrepancies.

A number of specific recommendations are included below, both short term (tactical) and longer term (strategic), which will be needed in order to expedite and synergize research efforts and move the experimental paradigm toward strategies that have the potential to ameliorate the consequences of FSHD. The recommendations are summarized below.

Short Term Objectives

I. Implement Web Research Resource
II. Create Uniform Research Reagents and Materials

The production of a series of uniform reagents should be undertaken for the purpose of providing consistent experimental materials:

A. Antibodies
B. Cell Lines
There seems to be significant variability in many of the studies resulting from the source of material being analyzed. Much of this is suspected as arising from the vagaries in the production of cell lines from tissue, induction of cellular morphogenesis, and the source of material. It seems critical that a universal source of materials and protocols capable of producing consistent results be available to all researchers to baseline their studies.

1. Derived from tissue.
2. Cell lines derived from matched materials (e.g. fibroblast, lymphoblast) should also be collected, archived and distributed.
3. Establish a consistent set of protocols capable of producing reproducible outputs with a characterized set of cell lines.
4. Encourage the deposition of all cell lines in an established repository such as the Human Cell Repository at the Coriell Institute, and require it for cell lines produced with FSH Society funds (see below).
5. Investigators should be required to use these “base-line” reagents in addition to any of their own that they may generate.

C. Animal Models
Rapid access to potential models of disease is critical to confirm the validity of the model, for hypothesis testing and to begin to develop therapeutic strategies to cure or ameliorate the consequences of disease.

III. Generating Sequence On Disease Specific Alleles

Generating sequence on ‘disease specific’ alleles. This is a topic that has come up several times in recent years with no clear progress. This may be an area were we initiate a contract to complete this project. It is, potentially, of interest to the NIH Human Genome Research Institute.

IV. Enforcing Sharing and Propagation of Funded Research

Grant applications should include a statement describing a plan to make available research resources in the form of: mice strains, cell lines, antibodies, probes, sequence information, etc.

Long Term Objectives

I. Establish Robust Natural History for FSHD
II. Recapitulate FRG1 Mouse Using Tet-On like construct
III. Move FSHD Research to Systems Biology Approach

Position the research community for a systems biology approach. It is clear that the biological foundation for FSHD is complex and non-trivial. This picture is further obscured by the vagaries of individual laboratories’ technical nuances. Systems Biology is not a new discipline, as some might believe, but rather the reciprocal view of the reductionist approach to holistically evaluate a biological system with the aid of advanced computer technology. The challenge is that even advanced computer technology is still evolving when it comes to collecting and analyzing rich biological data sets that extend on a scale from the interaction of two molecules to a community of organisms. The complexity of the problem is further heightened in a non-biological way when the data being analyzed is of heterogeneous types generated at widely distributed sites. The key to success in such an endeavor is, therefore, constraining the irrelevant complexity and biological richness that the computational systems must deal with. One way that this is can be done is with controlled ontologies, defined platforms, experimental consensus, and distributed data structures. As described above, the implementation of a whole-on “Systems Approach” will require an unprecedented level of collaboration and cooperation. It is clear that such an endeavor can only accomplished between investigators working in an environment of trust and driven by altruistic motives.