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Hum Gene Ther. 2018 Jul;29(7):771-784. doi: 10.1089/hum.2017.154. Epub 2018 Mar 20.

Synthetic Adeno-Associated Viral Vector Efficiently Targets Mouse and Nonhuman Primate Retina In Vivo.

Carvalho LS1,2,3,4, Xiao R1,2,3,4, Wassmer SJ1,2,3,4, Langsdorf A2,4, Zinn E1,2,3,4, Pacouret S1,2,3,4,5, Shah S1,2,3,4, Comander JI2,4, Kim LA3,4, Lim L4, Vandenberghe LH1,2,3,4,6.

Author information

1
1 Grousbeck Gene Therapy Center, Boston, Massachusetts.
2
2 Ocular Genomics Institute , Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
3
3 Schepens Eye Research Institute, Boston, Massachusetts.
4
4 Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
5
6 INSERM UMR 1089, University of Nantes, Nantes University Hospital , Nantes, France .
6
5 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.

Abstract

Gene therapy is a promising approach in the treatment of inherited and common complex disorders of the retina. Preclinical and clinical studies have validated the use of adeno-associated viral vectors (AAV) as a safe and efficient delivery vehicle for gene transfer. Retinal pigment epithelium and rods-and to a lesser extent, cone photoreceptors-can be efficiently targeted with AAV. Other retinal cell types however are more challenging targets. The aim of this study was to characterize the transduction profile and efficiency of in silico designed, synthetic Anc80 AAVs for retinal gene transfer. Three Anc80 variants were evaluated for retinal targeting in mice and primates following subretinal delivery. In the murine retina Anc80L65 demonstrated high level of retinal pigment epithelium and photoreceptor targeting with comparable cone photoreceptor affinity compared to other AAVs. Remarkably, Anc80L65 enhanced transduction kinetics with visible expression as early as day 1 and steady state mRNA levels at day 3. Inner retinal tropism of Anc80 variants demonstrated distinct transduction patterns of Müller glia, retinal ganglion cells and inner nuclear layer neurons. Finally, murine findings with Anc80L65 qualitatively translated to the Rhesus macaque in terms of cell targets, levels and onset of expression. Our findings support the use of Anc80L65 for therapeutic subretinal gene delivery.

KEYWORDS:

adeno-associated virus; cone photoreceptors; gene therapy; in silico reconstruction; retina; retinal transduction

PMID:
29325457
PMCID:
PMC6066192
DOI:
10.1089/hum.2017.154
[Indexed for MEDLINE]
Free PMC Article

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