Innovative research aims to deepen understanding of the molecular cause of FSHD, with the goal of developing therapies
MDA has awarded two grants for research aimed at determining the precise molecular causes of facioscapulohumeral dystrophy (FSHD), and developing therapies for the disease.
MDA and Friends of FSH Research (FFSHR) based in Kirkland, Wash., will jointly fund a two-year, $200,000 grant to Joel Chamberlain, an assistant professor of medical genetics at the University of Washington in Seattle.
The second grant, funded entirely by MDA, also is slated for $200,000 over two years, and was awarded to Silvere van der Maarel, professor of medical genetics at Leiden (Netherlands) University Medical Center.
The funded projects are the result of a worldwide request for applications (RFA) issued by MDA and FFSHR in 2009, in an effort to stimulate innovative research into the causes and potential therapies for FSH dystrophy.
About the new grants
Both projects take aim at more fully characterizing the genetic cause of FSHD, identified in the early 1990s: a shorter than normal stretch of genetic code in an area called D4Z4 on chromosome 4. Although the shortened D4Z4 region was found to be associated with FSHD, the specific mechanisms underlying the disease have remained elusive. (For more information, see Impossible Things: Through the looking glass with FSH dystrophy researchers.)
Both projects also will look at potential therapeutic strategies for the disease. Their methods both center on RNA — chemical instructions produced from DNA which perform a number of crucial functions, including regulation of gene activity ("expression"), and various roles critical to the cell's protein-building process.
The focus of Joel Chamberlain's project is to utilize a natural cellular function called RNA interference, or RNAi, with which cells regulate the levels of proteins produced to maintain a healthy body.
The group plans to harness the RNAi process both as an investigative tool that will help probe the molecular underpinnings of the disease, and also as the basis for potential therapeutics. Specifically, the investigators will look to employ directed RNAi to turn off production of certain genetic messages that may be involved in bringing about FSHD.
Van der Maarel's project also is geared toward modulating RNA, but his group's strategy will incorporate the use of molecules called antisense oligonucleotides, or AONs, to target the splicing process, which is crucial for proper regulation of gene activity in the D4Z4 region, and which appears to be dysregulated in FSHD.
Comprised of short laboratory-manufactured stretches of genetic code, AONs bind to targeted sections of RNA; this alters the way immature RNA molecules become processed into the final genetic information that the cell can use.
The group plans to design AONs and test them in cell culture (laboratory-based) experiments and also in a mouse model engineered to have an FSHD-like disease.
Meaning for people with FSHD
Both the Chamberlain and van der Maarel projects aim to get directly at the root molecular cause of FSHD. Importantly, the tools they use to do it, RNAi and antisense oligonucleotides, potentially may turn out to be the therapeutic agents that will then treat the disease.
These projects still are in the early stages of research and are not close to human trials at this point. Much work in cell culture experiments will be needed, followed by proof-of-principle testing in animal models, before any testing can be initiated in humans.
It’s promising that both antisense and RNAi strategies are being widely developed and tested for a variety of diseases besides FSHD. (For example, MDA is supporting testing of antisense in Duchenne muscular dystrophy.) The knowledge gained from all these studies has the potential to hasten development of these types of therapeutics in FSHD — for example, by demonstrating how best to deliver the therapy to targeted cells.