CureDuchenne - Together we Can CureDuchenne
July 2012

Scientist of the Month

Kevin Flanigan, MD
Kevin Flanigan, MD

CureDuchenne has been very interested in rare mutations, especially duplication mutations. We were very happy to support Dr. Kevin Flanigan’s project that is looking into exon skipping for duplication mutations in Duchenne. Here, Dr. Flanigan describes this project:

"In our work we are concentrating on the possibility of adapting exon skipping therapies for use in patients with DMD due to duplications of one or more exons within the dystrophin gene. Exon skipping therapies are directed toward the acting during the assembly of the messenger RNA (mRNA), which is the final blueprint for the production of a protein. Currently, exon skipping therapies are directed toward deletion mutations within the gene. The principle is that an additional exon is removed during the assembly of the mRNA, resulting in a larger deletion but also resulting in an mRNA that can be translated into a functional, Becker muscular dystrophy (BMD)-like version of the dystrophin protein.

In this research project, which is supported by CureDuchenne, we are exploring the feasibility of using exon skipping to correct duplication mutations. Here, the removal of one copy of a single duplicated exon would result in a normal dystrophin mRNA, rather than a BMD-like mRNA. As part of this work, we are establishing a novel mouse model that contains a duplication of exon 2 in the DMD gene. This is the most common single exon duplication in humans. We now have mouse pups that carry this mutation, and we look forward to expanding the mouse colony in order to establish how useful this mouse is as a tool for our studies. Our timeline for this is that over the next six to nine months we will complete all of the breeding to establish sufficient males to begin determine how severe the mouse’s muscle disease is. Over the following six to nine months we anticipate performing the actual exon skipping experiments, using both antisense oligomers and adeno-associated virus mediated mechanisms of exon skipping.

We hope that our work will be applicable to more patients than simply those with a single exon duplication. We have already established that certain duplicate exons may be removed as a single unit during exon skipping, and we are exploring this in cell lines derived from patients. We have established several such cell lines, and we are in the process of immortalizing them for use by researchers worldwide."

Kevin M. Flanigan, MD, is an attending neurologist at Nationwide Children’s and Professor of Pediatrics at The Ohio State University College of Medicine. Certified by the American Board of Psychiatry and Neurology, Dr. Flanigan is a principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s. His primary research interest is in the genetic and molecular characterization of inherited neuromuscular diseases, and the development of therapies directed toward these diseases. A major focus of his laboratory concerns genotype/phenotype correlation in, with the intention of increasing our understanding of the pathogenesis in this disease and translating this understanding into improved therapies.