Abstract
Purpose :
Suprachoroidal injection is an emerging minimally inflammatory approach for delivery of drugs to the retina, including gene therapies. However, the evaluation of adeno associated virus (AAV) capsid tropism after suprachoroidal space (SCS) delivery has been constrained by the limited number of device options available to reach this space. We herein evaluated the ability of AAV2 to transduce the NHP retina four weeks after delivery by the Everads suprachoroidal delivery device system (SDDS) that employs a novel approach by creating a channel to the choroid via blunt dissection of the scleral and choroidal tissues.
Methods :
In this study, cynomolgus macaques were administered AAV2-GFP (Green Fluorescent Protein, 5E11 vector genomes per eye in a volume of 120 µL) into the SCS with the Everads SDDS. The compatibility of AAV2-GFP with the Everads SDDS was confirmed. Animals were confirmed negative for AAV2 neutralizing antibodies before dosing. Animals were monitored for intraocular pressure (IOP), confocal scanning laser ophthalmoscopy (cSLO) for GFP expression and by optical coherence tomography (OCT) for retinal or choroidal changes. At 4 weeks post-dosing, ocular tissues were evaluated for vector genomes (qPCR), mRNA (RT-qPCR) and GFP protein (IHC).
Results :
The SCS injections were well tolerated, with no retinal or choroidal changes observed by OCT at either 1- or 4-weeks post injection. By IHC, AAV2 showed robust RPE transduction circumferentially from injection site, around to the posterior pole, past the macula, and into the nasal retina. In-life assessments detected GFP expression in the parafovea ring, confirmed with IHC, indicating transduction to the retinal ganglion cell (RGC) layers. Biodistribution confirmed VGs in retina, choroid-RPE, sclera, and ciliary bodies, with the highest mRNA expression in retina, choroid-RPE and ciliary bodies.
Conclusions :
Administration of AAV2-GFP with the Everads SDDS was well tolerated. Circumferential transduction occurred past the posterior pole, and across layers of the retina beyond the RPE. Overall, these findings indicate the ability of the Everads SDDS to deliver therapies to the suprachoroidal space, and for AAV2 to target multiple layers of the retina that would be beneficial for the treatment of retinal diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.