Trans-splicing adeno-associated viral vector-mediated gene therapy is limited by the accumulation of spliced mRNA but not by dual vector coinfection efficiency

Human Gene Therapy
Zhuping XuDongsheng Duan

Abstract

Therapeutic application of recombinant adeno-associated virus (AAV) has been limited by its small carrying capacity. To overcome this limitation trans-splicing vectors were developed recently. However, the transduction efficiency of trans-splicing vectors is considerably lower than that of a single intact vector in skeletal muscle. To improve trans-splicing vectors for skeletal muscle gene therapy, we examined whether coinfection efficiency is a rate-limiting factor in the mdx mouse, a model for Duchenne muscular dystrophy. Two different AAV viruses were delivered to the mdx muscle. Similar to previous reports in normal muscle, coinfection efficiency reached approximately 90% in the diseased muscle. This result suggests that coinfection is not a hurdle in dystrophic muscle. Another critical step in the trans-splicing method is the transcription and splicing across the inverted terminal repeat (ITR) junction in the reconstituted genome. To test whether this represented a significant obstacle, we systematically evaluated the transcription, pre-mRNA stability and splicing, and translation in a synthetic lacZ construct that mimicked the reconstituted genome. Although inserting an intron in the lacZ gene had no effect on its express...Continue Reading

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Citations

Apr 14, 2006·Human Genetics·Kenneth H Warrington, Roland W Herzog
Nov 12, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yi LaiDongsheng Duan
Oct 26, 2005·Nature Biotechnology·Yi LaiDongsheng Duan
Feb 1, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Arkasubhra GhoshDongsheng Duan
Feb 16, 2010·Human Molecular Genetics·William LostalIsabelle Richard
Aug 13, 2011·Journal of Translational Medicine·Jin-Hong ShinDongsheng Duan
Nov 6, 2009·PloS One·Matthew L HirschR Jude Samulski
May 11, 2011·Molecular Medicine·Florian BarthélémyMarc Bartoli
May 1, 2013·International Journal of Nanomedicine·Satya Ranjan SarkerShinji Takeoka
Mar 4, 2014·Human Gene Therapy·William LostalDongsheng Duan
Jun 2, 2015·Molecular Therapy. Methods & Clinical Development·Marina PryadkinaIsabelle Richard
Apr 26, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Hatem ZayedBruce R Blazar
Aug 14, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Matthew L HirschRichard Jude Samulski
Nov 7, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Arkasubhra GhoshDongsheng Duan
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Dec 7, 2007·Biotechnology & Genetic Engineering Reviews·Arkasubhra Ghosh, Dongsheng Duan
Apr 6, 2021·Frontiers in Neuroscience·Ryan CraneMuna I Naash
Aug 28, 2021·Biomolecules·Bhubanananda SahuHemant Khanna

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