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Outer retinal transduction by AAV2-7m8 following intravitreal injection in a sheep model of CNGA3 achromatopsia

Gene Therapy volume 29, pages 624–635 (2022)Cite this article

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Abstract

Sheep carrying a mutated CNGA3 gene exhibit diminished cone function and provide a naturally occurring large animal model of achromatopsia. Subretinal injection of a vector carrying the CNGA3 transgene resulted in long-term recovery of cone function and photopic vision in these sheep. Research is underway to develop efficacious vectors that would enable safer transgene delivery, while avoiding potential drawbacks of subretinal injections. The current study evaluated two modified vectors, adeno-associated virus 2-7m8 (AAV2-7m8) and AAV9-7m8. Intravitreal injection of AAV2-7m8 carrying enhanced green fluorescent protein under a cone-specific promoter resulted in moderate photoreceptor transduction in wild-type sheep, whereas peripheral subretinal delivery of AAV9-7m8 resulted in the radial spread of the vector beyond the point of deposition. Intravitreal injection of AAV2-7m8 carrying human CNGA3 in mutant sheep resulted in mild photoreceptor transduction, but did not lead to the clinical rescue of photopic vision, while day-blind sheep treated with a subretinal injection exhibited functional recovery of photopic vision. Transgene messenger RNA levels in retinas of intravitreally treated eyes amounted to 4–23% of the endogenous CNGA3 levels, indicating that expression levels >23% are needed to achieve clinical rescue. Overall, our results indicate intravitreal injections of AAV2.7m8 transduce ovine photoreceptors, but not with sufficient efficacy to achieve clinical rescue in CNGA3 mutant sheep.

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Fig. 1: eGFP expression in sheep retinas evaluated in vivo by fluorescent fundus photography and postmortem by immunohistochemistry (IHC).
Fig. 2: Composite fundus photography and fluorescent fundus photography showing the radial spread of AAV9-7m8-PR.1.7-eGFP injected SR in two peripheral locations.
Fig. 3: Electroretinography and behavioral maze test results of CNGA3 mutant sheep injected IVT and SR with AAV2-7m8-PR.1.7-hCNGA3.
Fig. 4: Immunohistochemistry of a representative CNGA3 mutant sheep retina (8730) injected IVT with AAV2-7m8-PR.1.7-hCNGA3.
Fig. 5: Relative quantification of hCNGA3 transgene expression following SR and IVT injections of AAV2-7m8-PR.1.7-hCNGA3.

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Funding

This study was funded by grants from the Israel Science Foundation (1257/15) and the Chief Scientist Office, Ministry of Health (3-15068), awarded to RO, and ERC Starting Grants (REGENETHER 639888/D.D.), the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université, the Agence Nationale pour la Recherche—Recherche Hospitalo-Universitaire en santé (RHU; Light4Deaf), LabEx LIFESENSES (ANR-10-LABX-65), *IHU FOReSIGHT (ANR-18-IAHU-01), awarded to DD, and from Research to Prevent Blindness (USA) awarded to EB.

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Author notes

  1. These authors contributed equally: D. Dalkara, R. Ofri.

Authors and Affiliations

  1. Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

    M. Ross, R. Ezra-Elia & R. Ofri

  2. Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    A. Obolensky, E. Averbukh, E. Yamin & E. Banin

  3. Department of Therapeutics, Institut de la Vision, Paris, France

    M. Desrosiers & D. Dalkara

  4. Department of Animal Science, ARO, The Volcani Center, Rishon LeZion, Israel

    H. Honig, A. Rosov, H. Dvir & E. Gootwine

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Contributions

MR and RO wrote the manuscript, which was reviewed by all authors; MR and AO conducted the IHC studies; EA, EB, HH, and EY operated on the animals; MD and DD designed and produced the vectors, and developed the serological tests; MR and RE-E conducted the ERG recordings; RM conducted the PCR and serology studies; EG, HD, and AR were responsible for breeding and maintaining the experimental animals and conducting the maze tests; RO, DD, EB, and EG wrote the grants that funded this study.

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Correspondence to R. Ofri.

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Competing interests

DD is co-inventor on patent #9193956 (Adeno-associated virus virions with variant capsid and methods of use thereof), with royalties paid to Adverum Biotechnologies and on pending patent applications on noninvasive methods to target cone photoreceptors (EP17306429.6 and EP17306430.4) licensed to Gamut Tx. DD is a founder and acting CSO of Gamut Tx. The other authors declare no competing interests.

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Ross, M., Obolensky, A., Averbukh, E. et al. Outer retinal transduction by AAV2-7m8 following intravitreal injection in a sheep model of CNGA3 achromatopsia. Gene Ther 29, 624–635 (2022). https://doi.org/10.1038/s41434-021-00306-1

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