July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Immunological response and durability of expression following sequential intravitreal administration of AAV2.7m8 gene therapy to the contralateral eye in non-human primates
Author Affiliations & Notes
  • Diana Cepeda
    Adverum Biotechnologies, Menlo Park, California, United States
  • Edward Yeh
    Adverum Biotechnologies, Menlo Park, California, United States
  • Julio Nieves
    Adverum Biotechnologies, Menlo Park, California, United States
  • Carolina Ceballos Diaz
    Adverum Biotechnologies, Menlo Park, California, United States
  • Awilda Rosario
    Adverum Biotechnologies, Menlo Park, California, United States
  • Judith Greengard
    Adverum Biotechnologies, Menlo Park, California, United States
  • Claire Gelfman
    Adverum Biotechnologies, Menlo Park, California, United States
  • Mehdi Gasmi
    Adverum Biotechnologies, Menlo Park, California, United States
  • Footnotes
    Commercial Relationships   Diana Cepeda, Adverum Biotechnologies (E); Edward Yeh, Adverum Biotechnologies (E); Julio Nieves, Adverum Biotechnologies (E); Carolina Ceballos Diaz, Adverum Biotechnologies (E); Awilda Rosario, Adverum Biotechnologies (E); Judith Greengard, Adverum Biotechnologies (E); Claire Gelfman, Adverum Biotechnologies (E); Mehdi Gasmi, Adverum Biotechnologies (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2910. doi:
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      Diana Cepeda, Edward Yeh, Julio Nieves, Carolina Ceballos Diaz, Awilda Rosario, Judith Greengard, Claire Gelfman, Mehdi Gasmi; Immunological response and durability of expression following sequential intravitreal administration of AAV2.7m8 gene therapy to the contralateral eye in non-human primates. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2910.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The adeno-associated viral (AAV) capsid AAV2.7m8 can transduce the retina following intravitreal (IVT) injection, which offers improved safety and convenience over subretinal injection, but introduces the vector into a less immune-privileged compartment. Some diseases, including wet age-related macular degeneration (wAMD), present at different times in each eye. Sequential IVT therapy risks development of neutralizing antibodies (nAbs) following treatment of the first eye which could reduce efficacy of IVT therapy in the second eye. To assess this risk, we investigated the effect of prior exposure of AAV2.7m8-aflibercept in one eye on transduction efficacy of the same AAV vector in the contralateral eye of nonhuman primates (NHPs).

Methods : African green monkeys (AGMs), prescreened for the absence of pre-existing serum nAbs cross-reactive to AAV.7m8, were dosed IVT in one eye with 2E12vg AAV2.7m8-aflibercept, and 8 weeks later the contralateral eye received an equal IVT dose of the same AAV vector. Aflibercept expression was monitored by ELISA in vitreous and aqueous fluids throughout the study duration up to 37 weeks, and in ocular tissue at study termination. Serum and vitreous nAbs were assessed at various time points post dosing.

Results : Sustained aflibercept expression in the first eye was detected in vitreous and aqueous humor at concentrations previously observed in AGMs, from the first time point evaluated at 8 weeks post-injection, through intermediate time points up to 37 weeks, the last time point evaluated. There was an increase in post-injection AAV.7m8 nAb levels in both serum and vitreous fluids. Aflibercept expression in the second eye at equivalent time points following injection was on average 3-fold lower than in the first eye. Mild inflammation was observed in both eyes, with second injection resulting in earlier onset likely due to recall immune response.

Conclusions : Our data demonstrate that development of immunity following IVT administration of AAV2.7m8 capsid in one eye does not completely block transduction following sequential dosing in the contralateral eye. Findings from this NHP study could prove valuable when designing AAV-mediated gene therapy protocols to treat wAMD patients with pre-existing vector immunity, or those with bilateral disease.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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