QTA020V, a novel rAAV2 vector, reduces retinal ganglion cell body and axon loss in rats with laser-induced intraocular pressure elevation

Abstract

Purpose : Brain-derived neurotrophic factor (BDNF) protects retinal ganglion cells (RGCs) in animal models of glaucoma, but chronic efficacy is compromised by TrkB receptor down-regulation. The rAAV2 vector, QTA020V, which generates mature BDNF (mBDNF) and TrkB receptors in RGCs, was examined for its ability to reduce loss of RGCs and axons in rats with laser-induced intraocular pressure (IOP) elevation.

Methods : Adult Sprague Dawley rats were injected intravitreally with QTA020V (TrkB-viral-2A-mBDNF) at low (1x10e9 viral particles(VP)/eye) or high (1x10e10 VP/eye) titre or with a Null control vector (1x10e10 VP/eye). Unilateral IOP elevation was induced by trabecular laser treatment and IOP measured for 6 weeks post-injury. Surviving Brn3A labelled RGCs were counted in retinal flat-mounts in central and peripheral regions at 6 weeks. Axon counts were performed using semi-thin optic nerve (ON) sections. Data is shown as mean±SD, analysed by ANOVA followed by Bonferroni modified t-tests.

Results : Laser treatment increased IOP to around of 40mmHg equally in all treatment groups which returned to baseline levels within 7 days and rose again following a second laser treatment. IOP elevation produced a significant reduction in average RGC density throughout the retina compared to normotensive eyes (Null, 1129±114 RGC/mm²; control, 2253±428 RGC/mm², P<0.01). Hypertensive eyes injected with QTA020V at low or high titre increased RGC survival by 22% (1379±118 RGC/mm², n=7, not significant.) and 56% (1757± 37 RGC/mm², n=8, P<0.01) respectively, compared to Null vector. Greater RGC protection was seen in peripheral retina. RGC survival increased by 44% (Low titre, 1130±71 RGC/mm²) and 85% (High titre, 1456±146 RGC/mm², P<0.001) versus Null vector (785 ± 103 RGC/mm²). Optic nerve axonal survival exhibited a similar pattern of protection. Total RGC axon counts were reduced in IOP elevation eyes (Null; 56385 ± 6450 axons/ON) compared to normotensive eyes (90800±15981 axons/ON, P<0.01). QTA020V increased axonal survival by 22% (low titre, 68486±7482 axons/ON, not significant) and 40% (high titre, 78901±12370 axons/ON, P<0.01).

Conclusions : QTA020V, a dual vector construct expressing TrkB and mBDNF, significantly reduced RGC and axonal loss in rats with laser-induced IOP elevation. QTA020V is undergoing further assessment as a potential treatment for human glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.