Preclinical safety evaluation of subretinal AAV2.sFlt-1 in non-human primates

Abstract

We report on the long-term safety of AAV2.sFlt-1 (a recombinant adeno-associated virus serotype 2 carrying the soluble form of the Flt-1 receptor) injection into the subretinal space of non-human primates. Levels of sFlt-1 protein were significantly higher (Po0.05) in the vitreous of four out of five AAV2.sFlt-1-injected eyes. There was no evidence of damage to the eyes of animals that received subretinal injections of AAV2.sFlt-1; ocular examination showed no anterior chamber flare, normal fundus and electroretinography responses equivalent to those observed before treatment. Notably, immunological analysis demonstrated that gene therapy involving subretinal injection of AAV2.sFlt-1 does not elicit cell-mediated immunity. Biodistribution analysis showed that AAV2.sFlt-1 could be detected only in the eye and not in the other organs tested. These data indicate that gene therapy with subretinal AAV2.sFlt-1 is safe and well tolerated, and therefore promising for the long-term treatment of neovascular diseases of the eye.

Modulation of Transgene Expression in Retinal Gene Therapy by Selective Laser Treatment

“…The leading program in development uses recombinant adenoassociated virus (rAAV-2) encoding for sFlt-1, which is a highly potent and naturally occurring antiangiogenic peptide that binds and inactivates VEGF. Subretinal delivery of rAAV.sFlt-1 prevents and reverses progression of ocular neovascularization in mice and nonhuman primates, 5 and is currently the subject of a Phase 1/2 clinical trial for wet AMD (NCT01494805). In the longer term, AMD could also be addressed by treatments that target the complement pathway, as several complement proteins have been implicated in AMD.…”

Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development

“…Delivered intravitreally, AAV2.sFLT01 (Genzyme Corporation, Cambridge, MA, USA) can provide lasting anti-VEGF effects in neovascular AMD in a preclinical study involving nonhuman primates 82. This treatment modality has yet to be tested in humans.…”

Functional Characterization of AAV-Expressed Recombinant Anti-VEGF Single-Chain Variable FragmentsIn Vitro

“…24,25 Similar treatment strategies using the soluble variant of the VEGF-R (sFlt1) expressed in the primate retina after AAV-mediated gene transfer have already been evaluated and are currently verified in a clinical trial (clinicaltrials.gov: NCT01494805). 26,27 However, the endogenous physiological role of sFlt1 is still only incompletely understood, which renders the use in treatment approaches problematic.…”