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- W1544316897 abstract "OBJECTIVES: To utilize a novel AAV gene delivery approach requiring homologous recombination to deliver full-length dysferlin safely with restoration of function.BACKGROUND: Dysferlin deficiency causes defects in muscle membrane repair in LGMD2B. The dysferlin gene (DYSF) cannot be packaged in AAV because of size limitations. Pre-clinical studies using adeno-associated virus (AAV) type rh74 show that recombination events can deliver the full-length DYSF gene to dysferlin-null mice (129-Dysf-/-KO). In the present study we compared efficiency and safety of dual vector DYSF delivery in this mouse model and in non-human primates in preparation for clinical trialsMETHODS: Dysferlin cDNA was packaged into AAVrh74 utilizing a dual vector (DV) strategy. One vector contains the MHCK7 promoter and 5’ half of dysferlin; the second vector contains the 3’ half of dysferlin. To assess membrane repair, ascending vector doses were delivered to the flexor digitorum brevis (FDB) of DYSF-null mice. In NHPs dual vector delivery was followed for both gene expression and toxicity using a biomarker (FLAG) to ensure gene delivery.RESULTS: 10wks post-treatment, the FDB was extracted from DYSF-null mice and sarcolemmal damage was induced by laser to individual muscle fibers. DYSF recombination events using AAVrh74 and the MHCK7 promoter corrected membrane repair in a dose-dependent manner comparable to wild-type findings. Importantly, in preparation for clinical trials, there was no evidence of local or systemic toxicity in DYSF-null mice or non-human primates in gene recipients showing overexpression of dysferlin.CONCLUSIONS: Recombination events are required to deliver the full-length transcript of DYSF, too large for AAV packaging. Findings in mice showed clear evidence that functional dysferlin was delivered, transcribed and translated without toxicity. Studies in non-human primates further confirmed both expression and lack of toxicity. These studies lay the foundation for clinical trial.Study Supported by: The Jain Foundation and Nationwide Children9s Hospital Disclosure: Dr. Sondergaard has nothing to disclose. Dr. Pozsgai has nothing to disclose. Dr. Griffin has nothing to disclose. Dr. Mendell has received research support from Sarepta Therapeutics Inc. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics." @default.
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- W1544316897 date "2014-04-08" @default.
- W1544316897 modified "2023-09-22" @default.
- W1544316897 title "AAV Gene Transfer Utilizing Homologous Overlap Vectors Mediates Functional Recovery of Dysferlin Deficiency (S61.004)" @default.
- W1544316897 hasPublicationYear "2014" @default.
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