Re-engineering a Transmembrane Protein to Treat Muscular Dystrophy Using Exon Skipping

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dc.contributor.advisor McNally, Elizabeth M Gao, Quan 2016-10-26T21:38:20Z 2016-10-26T21:38:20Z 2015 2015
dc.identifier doi:10.6082/M1X63JTS
dc.description The dystrophin complex is a multi-protein complex that has both structural and signaling roles in cardiac and skeletal muscle. Loss-of-function mutations in the genes encoding dystrophin, or the associated sarcoglycan proteins, lead to myofiber loss and muscle degeneration. The structure-function correlation between predicted protein structure and clinical outcomes has been extensively cataloged for dystrophin mutations. Studies in animal models also shed light on the dystrophin regions necessary for in vivo function. Together, these findings provided the justification for testing exon skipping strategies to restore dystrophin protein in human patients. Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. With exon skipping, antisense oligonucleotides target RNA to bypass premature stop codons and restore reading frame disruption. Exon skipping is currently being evaluated in humans with Duchenne Muscular Dystrophy and dystrophin gene mutations. For Duchene Muscular Dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We now expanded the potential for exon skipping by testing the functionality of an internal, in-frame deletion of a transmembrane protein, γ-sarcoglycan. We generated Mini-gamma by deleting a large portion of the extracellular domain, and showed that Mini-Gamma provided functional and pathological benefit to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. Since Mini-Gamma represents removal of four of the seven coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.
dc.format.extent 142
dc.format.mimetype PDF
dc.language.iso en_US
dc.publisher University of Chicago
dc.rights University of Chicago dissertations are covered by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission.
dc.subject antisense oligos
dc.subject dystrophin complex
dc.subject exon skipping
dc.subject muscular dystrophy
dc.subject sarcoglycan
dc.subject SGCG
dc.title Re-engineering a Transmembrane Protein to Treat Muscular Dystrophy Using Exon Skipping
dc.type Dissertation
dc.contributor.department Developmental Biology Ph.D.

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