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Please use this identifier to cite or link to this item: http://hdl.handle.net/1860/1869

Title: Treatment of Duschenne Muscular Dystrophy with exon skipping antisense oligonucleotides using novel polyethylenimine carriers
Authors: Sirsi, Shashank Ramesh
Keywords: Biomedical engineering;Muscular dystrophy;Exons (Genetics)
Issue Date: 11-Oct-2007
Abstract: Duchenne muscular dystrophy (DMD) is a lethal disorder that is caused by mutations in the gene encoding the dystrophin protein. It has been established that exon skipping oligonucleotides (ESOs) are able to ameliorate the symptoms of DMD by modulating dystrophin pre-mRNA transcript splicing resulting in removal of the mutated exon from the mRNA transcript. It is estimated that up to 75% of DMD cases may be treatable using this ESO-based approach. However, the main obstacle that has limited the usefulness of ESOs in treatment of DMD, and most other diseases, is a lack of adequate carriers that enable ESO delivery to the target cell nuclei. Thus, for the ESO-based approach to ultimately provide clinical benefit in treating DMD, it is essential that new compounds be developed that improve the efficiency of ESO delivery to myonuclei. In this project, amine rich poly(ethylene imine) (PEI) based compounds were developed to improve the delivery of ESO’s to myonuclei of dystrophin-null muscle and recover the dystrophin protein. PEI is considered one of the most potent non-viral agents for nucleotide delivery; however, the feasibility of PEI-based compounds for the transfection of mature skeletal muscle has not been established. Alone, PEI is considered to be a cytotoxic compound, but the biocompatibility of PEI is significantly improved by incorporating nonionic linear polyethylene glycol (PEG) polymers into PEGPEI copolymers. This project demonstrates that PEG-PEI compounds are potent and versatile vectors capable of delivering ESO’s to skeletal muscle in vitro and in vivo. The PEG-PEI based compounds developed in this work serve as a platform for developing even more potent “next generation” PEG-PEI compounds that have a realistic potential for treatment of DMD.
URI: http://hdl.handle.net/1860/1869
Appears in Collections:Drexel Theses and Dissertations

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