Finalizing a unifying model of FSHD: genetic, transcriptional, and developmental aspects

Investigators: Stephen Tapscott MD PhD, Daniel G Miller MD PhD

Category: Research - Basic

Official Title: Partnership Proposal for Joint Funding for FSHD

Drs Tapscott and Miller aim to use this grant to finalize the preliminary studies and applications to NIH for funding an international cooperative study on FSHD.

Contents

• What are the researchers aiming to do?
• How will the outcomes of the research benefit patients?
• Background information

What are the researchers aiming to do?

We propose to use funds from the Friends of FSH Research to generate additional preliminary data that will support an international and multi-investigator NIH application. Over the last five years, researchers in Seattle, Rochester, Minneapolis, and The Netherlands have focused on individual projects in order to determine the most appropriate areas of research focus to advance our understanding of the molecular pathology of FSH dystrophy. This exploratory phase of FSH research is nearing an end as this group of FSH researchers begins to focus on the very specific mechanisms of FSHD that they, together, have identified.

This funding is requested to finish the experiments necessary to provide compelling support for an application to NIH to support a five year project with the ultimate goal of identifying therapeutic approaches to FSHD. Funding provided through this proposal will help facilitate programmatic development within the Seattle based research consortium and broadly benefit the extended members of this group by increasing the likelihood of NIH funding, and providing specific research tools for their projects. Specific milestones of this application will include (1) the development and validation of one or more antibodies that specifically recognize DUX4, (2) identifying RNA transcripts that might cause FSHD, (3) generation of induced pleuripotent stem cells (iPS cells) from FSHD and control individuals that will be critical for future research, (4) identify sequence differences between FSHD permissive chromosomes and non-permissive chromosomes to focus studies on the regions that cause FSHD, (5) combine these preliminary studies into a multi-investigator and international collaborative application to NIH for FSHD funding.

How will the outcomes of the research benefit patients?

The mutation that causes FSHD has been known for many years but the mechanism through which that mutation causes FSHD has been elusive. Ultimately, this application seeks to determine the exact mechanism of FSHD. As a first step, this application seeks funds to finalize the preliminary studies aimed at identifying the molecular cause of FSHD. As a second step, the application seeks the funding necessary to maintain scientific progress and successfully compete for long-term NIH funding of an international group of FSHD researchers.

Background information

This is a description of a large collaborative research program that leverages the expertise, funding, and facilities of researchers all over the world. More importantly, it emphasizes collaboration among different groups and assures that efforts will not be duplicated. The funds previously provided by the Friends of FSH Research have made the development of this ambitious research proposal possible. These previously funded projects, together with other funding support, have led to the emergence of a new and compelling model for the cause of FSHD. The current support is requested to finalize specific aspects of this model to make an application to NIH competitive. A successful application to NIH will provide substantial validation of the new FSHD model in the research community and, hopefully, lead to a new consensus on the molecular cause of FSHD. If this is successful, then the focus of FSHD research can justifiably shift toward therapeutic development.

See resulting Nature Genetics publication Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.