Michael Kyba, associate professor of pediatrics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $358,227 over a period of three years to study muscle developmental deficits in facioscapulohumeral muscular dystrophy (FSHD). The new grant complements previous MDA-funded work by Kyba to identify and test experimental therapies in FSHD.

FSHD is caused by aberrant expression (activity) of a gene called DUX4, which is usually silenced in adult muscle tissue. DUX4 turns on other genes, and activity of these genes is believed to cause disease by multiple mechanisms, including direct toxicity, interference with normal cell function and provoking the immune system.

“The mechanism of muscle degeneration in FSHD is enigmatic,” Kyba says, since unlike other muscular dystrophies, there is apparently neither ongoing muscle fiber damage, nor ongoing regeneration. “The mechanism of how genetic changes actually lead to deteriorated muscle is still very unclear.”

To answer some of those questions, he has generated muscle cells from patient skin cells in order to study the effects of the mutation that causes FSHD. He will now use newly developed “gene-editing” technology to correct the FSHD mutation, and to compare muscle development between uncorrected and corrected cells.

“This project will shed light on the molecular mechanism underlying FSHD, and will provide tools for genetic correction of the FSHD mutation in cells in culture,” says Kyba. “Understanding the genetic mechanism is essential to developing rational pharmaceutical therapies for FSHD. In addition, with a view toward future cell therapies, having methods to correct the genetic mutation that causes FSHD will facilitate autologous (self) transplantation of genetically corrected cells.”

Funding for this MDA grant began Feb. 1, 2013.