James Ervasti, professor of biochemistry, molecular biology & biophysics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $390,000 over a period of three years to help support his research into improving two therapies currently in development for people with Duchenne (DMD) and Becker (BMD) muscular dystrophies.
Exon skipping is a strategy in which molecules called anstisense oligonucleotides (AONs) target error-containing parts of a gene and coax cells to retain the error-free parts for protein synthesis.
As with exon skipping, viral delivery of miniaturized dystrophin genes is designed to restore sufficient levels of the dystrophin protein, which is deficient in DMD and BMD.
Both strategies create non-natural versions of dystrophin, and Ervasti and colleagues have shown that the miniaturized dystrophin proteins are prone to misfolding, instability and clumping into aggregates — all of which likely limit their effectiveness.
In his new research, Ervasti will study ways to assess and optimize the stability of miniaturized dystrophin proteins in the laboratory before they are tested in animal models with dystrophin deficiency. Ervasti's team also will examine how exon-skipping strategies currently under investigation to treat DMD and gene deletions associated with BMD affect the stability of dystrophin.
A better understanding of how missing stretches of the dystrophin protein affect folding "may further allow us to identify drugs to treat patients with BMD and also enhance the effectiveness of exon skipping approaches," Ervasti said.
Funding for this MDA grant began February 1, 2012.
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