Intravitreal delivery of AAV2.7m8.ranibizumab suppresses exudative lesions in the NHP laser induced model of nAMD

Abstract

Purpose : Intravitreal (IVT) injection of AAV-based gene therapies is an in-office procedure, suited better than subretinal surgery for patients with high prevalence retinal diseases such as age-related macular degeneration and diabetic retinopathy. We have previously demonstrated that IVT injection of ADVM-022, a gene therapy vector containing the AAV2.7m8 capsid optimized for high level intraocular expression of aflibercept, suppressed exudative lesions in the non-human primate (NHP) model of choroidal neovascularization (CNV). This result paved the way for the phase I OPTIC trial, which demonstrated consistent and sustained anatomical improvements on optical coherence tomography (OCT) in patients with nAMD following a single IVT injection of ADVM-022. In addition to demonstrating the efficacy of our clinical drug ADVM-022, in this study we have evaluated the efficacy of the AAV2.7m8 gene therapy vector expressing another anti VEGF protein (ranibizumab) delivered intravitreally two months prior to laser-induced CNV in NHPs.

Methods : Animals received an IVT injection of AAV2.7m8.ranibizumab 56 days prior to laser photocoagulation. CNV was assessed 2 and 4 weeks post-laser by fluorescein angiography and OCT. Efficacy was compared to vehicle and ranibizumab protein bolus treated animals. Levels of ranibizumab were quantified from the aqueous and vitreous humor.

Results : A single IVT injection of AAV2.7m8.ranibizumab resulted in sustained ranibizumab expression (measured out to 140 days, the last time point evaluated) ranging from 74 to 326 ng/mL in aqueous humor and 374 to 1574 ng/ml in vitreous humor. AAV2.7m8.ranibizumab significantly inhibited the formation of exudative Grade IV lesions when compared to vehicle-treated eyes (25% and 24% in the vehicle-treated group compared to 2% and 0% for AAV2.7m8.ranibizumab, measured 2 and 4 weeks post-laser, respectively; p < 0.0001). The effect was comparable to efficacy observed following an IVT bolus of recombinant ranibizumab delivered immediately after the laser, and was confirmed by the reduction in size of fibrovascular complexes measured by OCT.

Conclusions : This work, together with the published preclinical results of ADVM-022, highlights the utility AAV2.7m8 as an effective gene therapy platform for the intravitreal delivery of anti-VEGF therapeutic proteins, and as such has demonstrated its potential for the treatment of CNV.

This is a 2020 ARVO Annual Meeting abstract.