Exon Skipping Gene Therapy for Duchenne Muscular Dystrophy

by Dr. Hsien-Hsien Lei
Posted October 18, 2007 in DNA and Disease, Gene Therapy

Gene therapy corrects defective genes by inserting a normal one, repairing specific mutations, or regulating gene function. One new way specific genetic mutations can be targeted is by skipping them altogether. AVI BioPharma is developing exon skipping genetic technology, called ESPRIT (exon skipping pre–RNA interference technology), that can sidestep mutations that result in nonfunctioning or malfunctioning proteins. Duchenne muscular dystrophy (DMD) is the first genetic disorder in which ESPRIT will be tested.

Preclincial studies have shown that AVI’s NeuGene compounds can target the faulty exon, snip it out like fine genetic surgery, and force the cell machinery to skip over the fault and continue to splice and translate. The result is a form of dystrophin able to convert DMD to a form of the disease similar to the naturally–occurring and less severe BMD.

Earlier this week, Charley’s Fund, Inc. awarded a $2.45 million research grant to AVI BioPharma to develop ESPRIT. Charley’s Fund is named for Charley Seckler who was diagnosed with DMD in July 2004. He is one of over 15,000 to 20,000 boys in the United States who have the genetic disorder. Current treatments include steroids and stretching but most DMD kids die in their late teens or early twenties.

Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene on the X chromosome, one of the longest human genes. Because the gene is X-linked, boys are affected disproportionately; boys only have one X chromosome while girls have the protective effect of a normal dystrophin gene on the second of their X chromosomes. A normal dystrophin protein gives muscle cells strength and stability in addition to playing a role in carrying cell signals.

AVI has applied ESPRIT to diseases other than DMD. Exon skipping may also be a useful technique for treating type 1 diabetes, multiple sclerosis, and other inflammatory disorders.

Image: Duchenne muscule dystrophy deletion, FISH. Human chromosomes highlighted by fluorescent probes which bind to specific sequences of DNA. The FISH (fluorescence in situ hybridisation) study is of a female heterozygous for a deletion in the Duchenne muscular dystrophy (DMD) gene. The DMD cosmid probe is red, the X chromosome centromeres are green. via Wellcome images under Creative Commons.

Tags: duchenne muscular dystrophy, dmd, dystrophin gene, charley’s fund, avi biopharma, genetics, genes, dna, medicine, health, gene therapy, diseases

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