Biomarkers for Therapy of FSHD

Principal Investigator: Kathryn Wagner

The goal of this Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center is to define modifying genes of FSHD and to determine, through novel animal models of FSHD, whether these are appropriate therapeutic targets. 1) Our current research will seek to identify genetic modifiers of Facioscapulohumeral muscular dystrophy by focusing on nonmanifesting earners of the 4qA allele. These individuals suggest that the current genetic signature of FSHD (D4Z4 contraction in the presence of the 4qA allele and a polyadenylation sequence in a distal pLAM sequence) is not an exclusive determinant of FSHD and that there is either a "second-hit" resulting in disease or a protective gene resulting in muscle health. 2) In the animal models of FSHD, our research aims to use xenografts of mouse and human muscle as well as a zebrafish model of DUX4 misexpression during development. The humanized mouse muscle either by direct engraftment of human skeletal muscle or with cell transplantation provides human muscle in a living organism on which to develop therapeutic approaches. The models should allow the search for modulators of DUX4-fl expression and any key developmental targets of DUX4-fl expression. In addition, the latter should result in an understanding of the generation of clinical symptoms outside skeletal muscle. Knock down of Dux4-fl through AAV as well as morpholino administration will be developed in the xenografts with the ultimate goal of using these approaches in clinical trials.