Antisense Mediated Suppression of Dystrophin Mutations

University Of Utah, Salt Lake City UT

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Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Mutations in the X-linked dystrophin gene result in Duchenne Muscular Dystrophy (DMD), or the milder Becker Muscular Dystrophy (BMD). Since the initial characterization of the genetic defect responsible for this devastating childhood disease, a number of potential therapeutic approaches have received significant attention. Some examples include, gene therapy to deliver a wild type or mini-gene v version of dystrophin, myoblast or stem-cell therapy to introduce dystrophin producing cells, himeric oligonucleotides to correct the mutation, and antisense oligonucleotides designed to modify the mRNA during splicing. Another distinct approach, addressed in this proposal, is directed toward altering decoding (translation) of the mutant gene, such that expression of active full length protein is restored. As translation is mediated by the molecular machinery of the ribosome, restorative decoding therapies will be directed toward altering ribosomal function at some level. The overall goals of this project are to (1) identify ways to subvert the fidelity of the translational apparatus in a site-specific manner using antisense technology and small molecule drugs which target the ribosome, and (2) explore the utility of this approach for suppressing stop codon and frameshift mutations in the dystrophin gene. As current approaches to restorative decoding utilize compounds which cause wide-spread translational errors, a clear advancement in the field would be achieved by the ability to direct either reading frame restoration or stop codon readthrough to the site of a disease causing mutation. Finally, as proposed in this grant, demonstrating efficient and site-specific restorative decoding in primary cells isolated from mdx mice carrying frameshift and stop codon mutations in the dystrophin gene, will establish the rationale for future preclinical studies in these animals and in human cell culture models of muscular dystrophy. [unreadable] [unreadable]