Four-year follow up of intraocular pressure (IOP) control in a canine model of open-angle glaucoma (OAG) treated with adeno-associated virus (AAV)-mediated modification of gene expression within the aqueous humor outflow pathways (AHOP)

Abstract

Purpose : To demonstrate that gene enhancement therapy of the AHOP following a single intracameral AAV injection results in long-term stable IOP control by preventing extracellular plaque formation in the trabecular meshwork (TM) of a well-established canine OAG model.

Methods : Six ADAMTS10-mutant dogs with early stages of OAG were injected unilaterally with a 75-100μL volume of single-stranded AAV2(Y444F)-smCBA-hADAMTS10 vector (1.25-1.61 x 10¹² vector genomes). Clinical outcome measures were monitored for 24-48 months, including weekly diurnal IOP, repeated aqueous humor (AH) flow measurements, and high-resolution imaging of retina and optic nerve head (ONH) by optical coherence tomography (OCT). IOP analysis consisted of pairwise comparisons of treated vs. fellow control eyes while accounting for dog-to-dog variation. Safety monitoring included routine clinical ophthalmic examinations and AH analyses (protein concentrations, cell counts, and neutralizing AAV antibody titers). Ocular tissues were examined by routine light and transmission electron microscopy (TEM).

Results : IOP decreased significantly and was less variable for the entire 24- to 48-month observation period in 5/6 ADAMTS10-mutant dogs in treated vs. fellow control eyes (16.6±7.5 vs. 29.7±8.7 mmHg; p<0.0001). Outflow facility was significantly higher and more variable in treated (0.34±0.15) vs. untreated (0.23±0.08) eyes (p<0.01). OCT imaging showed that ONH morphology remained unchanged over time in successfully treated eyes, but degeneration/cupping progressed in untreated controls. Mild anterior uveitis with positive neutralizing antibody titers developed in the serum of all dogs as well as in the AH of AAV-treated but not untreated fellow eyes. TEM examination of the TM revealed almost complete prevention of extracellular plaque formation in treated vs. untreated eyes.

Conclusions : Long-term, stable IOP control can be achieved for at least 4 years following a single intracameral injection of AAV in a clinically relevant canine OAG model. These findings are consistent with reduced extracellular TM plaque formation and increased AH outflow facility.

This is a 2021 ARVO Annual Meeting abstract.