Glaucoma is an optic neuropathy that causes irreversible damage to retinal ganglion cell axons. Most forms of open angle glaucoma (OAG) are associated with an increased intraocular pressure (IOP) due to obstruction of the aqueous humor outflow pathways (AHOP). For years our team has worked to preserve vision by targeting these outflow pathways by delivering a novel capsid mutated adeno-associated virus (AAV) mediated gene replacement therapy in a clinically relevant and well-established OAG dog model caused by a mutation in ADAMTS10. Past studies with ssAAV2-(Y444F)- hGFP (targeting) and ssAAV2-(Y444F)- hADAMTS10 (therapy) at vector genome (vg) dose of 1-3x10 11 vg administered intracamerally (IC) in a 50æL volume delivered safe and long-term transgene expression to the AHOPs; however, an IOP reducing therapeutic effect was not achieved. Our goal was to increase transduction efficiency to the AHOPs by delivering the same vector constructs at a higher dose. In Aim 1, we showed in 5 dogs that 2.78-5.56x1012vg provided increased and clinically observable transgene expression within the iridocorneal angle (ICA). In Aim 2, 2 of 3 dogs IC injected with ssAAV2-( Y444F)-hADAMTS10 at 1.25-1.43x1012vg experienced a significant reduction in IOP by 19-20 days post-injection with a steady and well-maintained reduction for at least 105 weeks. ssAAV2-( Y444F)-hADAMTS10 was well-tolerated and resulted in an increased outflow facility by 3-75%. These studies provide proof-of-concept that modification of gene expression within the AHOP is possible and can result in long-term IOP control.
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