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mark S shearman, Elisha Gootwine, Eyal Banin, Ron Ofri, Raaya Ezra-Elia, Guo-jie Ye, Paulette Robinson, David Knop, Jeffrey D Chulay; Safety and Efficacy of AAV2tYF-PR1.7-CNGA3 in CNGA3-deficient Sheep. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4488.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia is an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. AGTC is developing AAV2tYF-PR1.7-CNGA3, a recombinant adeno-associated virus (rAAV) vector expressing CNGA3, for treatment of CNGA3-related achromatopsia. Here we report results of a toxicology and efficacy study of this vector administered by subretinal injection in CNGA3-deficient sheep.
Groups of 4 or 5 animals received a 0.5 mL subretinal injection in the right eye of AAV2tYF-PR1.7-CNGA3 at one of two dose levels or AAV5-PR2.1-hCNGA3, a vector previously shown to rescue cone photoreceptor responses. The left eye received a 0.5 mL subretinal injection of vehicle (4 animals) or was untreated (9 animals). Toxicity assessment was based on mortality, clinical observations, ophthalmic examinations, ERG, and clinical and anatomic pathology. CNGA3 expression was assessed by immunohistochemistry. Efficacy was assessed by cone ERG responses and maze navigation testing performed before, then 6 and 12 weeks after treatment.
Treatment was not associated with systemic toxicity. Most animals had mild to moderate conjunctival hyperemia, chemosis and subconjunctival hemorrhage immediately after surgery that generally resolved by post-operative Day 7. No clear and consistent test article-related effects were noted in any group during the 12 week study. Two animals treated with the higher dose of AAV2tYF-PR1.7-CNGA3 had microscopic findings of outer retinal atrophy, with or without inflammatory cells in the retina and choroid, that were procedural- and/or test article-related. All vector-treated eyes developed cone-mediated ERG responses with no change in rod-mediated ERG responses. Behavioral maze testing showed significantly improved navigation times and reduced numbers of obstacle collisions in all vector-treated eyes compared to their control eye or pre-dose results in the treated eye.
Subretinal injection of AAV2tYF-PR1.7-CNGA3 in CNGA3-deficient sheep was well tolerated with no clinically important toxicology findings. Rescue of cone-mediated ERG responses was recorded in all vector-treated eyes. These results support the use of AAV2tYF-PR1.7-CNGA3 in clinical studies in patients with achromatopsia caused by CNGA3 mutations. A Phase 1/2 clinical trial evaluating AAV2tYF-PR1.7-hCNGA3 is scheduled to begin in 2017.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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