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Gene Ther. 2016 Aug;23(8-9):680-9. doi: 10.1038/gt.2016.42. Epub 2016 Apr 26.

AAV-mediated transduction and targeting of retinal bipolar cells with improved mGluR6 promoters in rodents and primates.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
2
Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY, USA.
3
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
4
State University of New York, College of Optometry, New York, NY, USA.
5
Department of Ophthalmology, Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

Adeno-associated virus (AAV) vectors have been a powerful gene delivery vehicle to the retina for basic research and gene therapy. For many of these applications, achieving cell type-specific targeting and high transduction efficiency is desired. Recently, there has been increasing interest in AAV-mediated gene targeting to specific retinal bipolar cell types. A 200-bp enhancer in combination with a basal SV40 promoter has been commonly used to target transgenes into ON-type bipolar cells. In the current study, we searched for additional cis-regulatory elements in the mGluR6 gene for improving AAV-mediated transduction efficiency into retinal bipolar cells. Our results showed that the combination of the endogenous mGluR6 promoter with additional enhancers in the introns of the mGluR6 gene markedly enhanced AAV transduction efficiency as well as made the targeting more selective for rod bipolar cells in mice. Furthermore, the AAV vectors with the improved promoter could target to ON bipolar cells with robust transduction efficiency in the parafovea and the far peripheral retina of marmoset monkeys. The improved mGluR6 promoter constructs could provide a valuable tool for genetic manipulation in rod bipolar cells in mice and facilitate clinical applications for ON bipolar cell-based gene therapies.

PMID:
27115727
PMCID:
PMC4863234
DOI:
10.1038/gt.2016.42
[Indexed for MEDLINE]
Free PMC Article

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