Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors

Yi Lai; Yongping Yue; Mingju Liu; Arkasubhra Ghosh; John F Engelhardt; Jeffrey S Chamberlain; Dongsheng Duan

doi:10.1038/nbt1153

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Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors

Journal article

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Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors

Yi Lai, Yongping Yue, Mingju Liu, Arkasubhra Ghosh, John F Engelhardt, Jeffrey S Chamberlain and Dongsheng Duan

Nature biotechnology, Vol.23(11), pp.1435-1439

10/09/2005

DOI: 10.1038/nbt1153

PMCID: PMC2581721

PMID: 16244658

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https://www.ncbi.nlm.nih.gov/pmc/articles/2581721View

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Abstract

Although adeno-associated virus (AAV)-mediated gene therapy has been hindered by the small viral packaging capacity of the vector, trans -splicing AAV vectors are able to package twice the size of the vector genome. Unfortunately, the efficiency of current trans -splicing vectors is very low. Here we show that rational design of the gene splitting site has a profound influence on trans -splicing vector-mediated gene expression. Using mRNA accumulation as a guide, we generated a set of efficient trans -splicing vectors and achieved widespread expression of the 6-kb ΔH2-R19 mini-dystrophin gene in skeletal muscle of mdx mice, a model for Duchenne muscular dystrophy. The dystrophic phenotype was ameliorated in both adult and aged mice. This demonstrates the use of trans -splicing vectors to efficiently express a large therapeutic structural protein. This strategy should be applicable to other large therapeutic genes or large transcription regulatory elements.

Details

Title: Subtitle: Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors
Creators: Yi Lai - University of Missouri
Yongping Yue - University of Missouri
Mingju Liu - University of Missouri
Arkasubhra Ghosh - University of Missouri
John F Engelhardt - University of Iowa
Jeffrey S Chamberlain - University of Washington
Dongsheng Duan - University of Missouri
Resource Type: Journal article
Publication Details: Nature biotechnology, Vol.23(11), pp.1435-1439
DOI: 10.1038/nbt1153
PMID: 16244658
PMCID: PMC2581721
NLM abbreviation: Nat Biotechnol
ISSN: 1087-0156
eISSN: 1546-1696
Language: English
Date published: 10/09/2005
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984284336402771

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