Progress Update: Xenograft Mouse Model

by Robert J Bloch PhD
See grant: A Xenograft Model of FSHD for Testing Therapeutics

My laboratory has invested several years in developing methods for growing human skeletal muscle in mice, specifically with the aim of studying FSHD. Our methods, called “xenografting”, are now nearly optimal and have yielded several key discoveries. First, FSHD muscle tissue grows and matures in mice just like healthy muscle tissue. In fact, in histology studies it is very hard to distinguish the two. However, our second key finding has been that FSHD muscle can be recognized with an antibody to a protein called SLC34A2, which is responsible in part for regulating sodium and phosphate ion levels in mammalian cells. FSHD xenografts have about 1 fiber in 70 that contain significant amounts of SLC34A2, whereas control xenografts have only about 1 fiber in 1000. FSHD biopsies also show fibers that are positive for SLC34A2 much more frequently than biopsies of healthy muscle or muscles from individuals with other forms of muscular dystrophy. Notably, SLC34A2 is one of the genes that are turned on in the DUX4 program, responsible for FSHD. SLC34A2 is the first protein in the DUX4 program that any laboratory has reliably found to be elevated in mature FSHD muscle by histological methods, and thus it is a potentially very useful biomarker.

In addition to these advances, my laboratory has worked closely over the past 2 years with Fulcrum Therapeutics to test 2 different drugs that they had identified as being potentially useful in suppressing the DUX4 program. Working with Fulcrum, we showed that both drugs, Lilly compound LY2228820 and GSK’s losmapimod, effectively reduce DUX4 expression and the expression of several of DUX4’s target genes. Based in part on our results, Fulcrum has initiated a clinical trial to test the efficacy of losmapimod in treating FSHD.