Evaluation of Photoreceptor Transduction Efficacy of Capsid-Modified Adeno-Associated Viral Vectors following Intravitreal and Subretinal Delivery in Sheep

Maya Ross, Alexey Obolensky, Edward Averbukh, Raaya Ezra-Elia, Esther Yamin, Hen Honig, Hay Dvir, Alexander Rosov, William W. Hauswirth, Elisha Gootwine, Eyal Banin, Ron Ofri*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Gene augmentation therapy based on subretinal delivery of adeno-associated viral (AAV) vectors is proving to be highly efficient in treating several inherited retinal degenerations. However, due to potential complications and drawbacks posed by subretinal injections, there is a great impetus to find alternative methods of delivering the desired genetic inserts to the retina. One such method is an intravitreal delivery of the vector. Our aim was to evaluate the efficacy of two capsid-modified vectors that are less susceptible to cellular degradation, AAV8 (doubleY-F) and AAV2 (quadY-F+T-V), as well as a third, chimeric vector AAV[max], to transduce photoreceptor cells following intravitreal injection in sheep. We further tested whether saturation of inner limiting membrane (ILM) viral binding sites using a nonmodified vector, before the intravitreal injection, would enhance the efficacy of photoreceptor transduction. Only AAV[max] resulted in moderate photoreceptor transduction following intravitreal injection. Intravitreal injection of the two other vectors did not result in photoreceptor transduction nor did the saturation of the ILM before the intravitreal injection. However, two of the vectors efficiently transduced photoreceptor cells following subretinal injection in positive control eyes. Previous trials with the same vectors in both murine and canine models resulted in robust and moderate transduction efficacy, respectively, of photoreceptors following intravitreal delivery, demonstrating the importance of utilizing as many animal models as possible when evaluating new strategies for retinal gene therapy. The successful photoreceptor transduction of AAV[max] injected intravitreally makes it a potential candidate for intravitreal delivery, but further trials are warranted to determine whether the transduction efficacy is sufficient for a clinical outcome.

Original languageAmerican English
Pages (from-to)719-729
Number of pages11
JournalHuman Gene Therapy
Volume31
Issue number13-14
DOIs
StatePublished - 1 Jul 2020

Bibliographical note

Publisher Copyright:
© Copyright 2020, by Mary Ann Liebert, Inc., publishers 2020.

Keywords

  • AAV2 (quadY-F+T-V)
  • AAV8 (doubleY-F)
  • AAV[max]
  • intravitreal
  • retina
  • sheep

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