A new strategy of AAV-based gene therapy to treat glaucoma and ocular hypertension

L. Wu, C. Maturana, Z. Yao, W. Wang, B. Liang, L. Hong
IVIEW Therapuetics, Inc.,
United States

Keywords: Rho kinase, glaucoma, gene therapy, AAV


Glaucoma stands as a prominent contributor to irreversible blindness, presenting a formidable challenge for healthcare providers. Elevated intraocular pressure (IOP) is recognized as a significant risk factor in the development of glaucoma. While conventional treatments have demonstrated efficacy in reducing IOP, patient adherence to these interventions remains suboptimal. Gene therapy emerges as a promising avenue to tackle compliance issues, instilling renewed optimism for patients. The objective of this study was to create a new strategy of adeno-associated virus (AAV)-based gene therapy to mitigate IOP elevation by inhibiting the activity of Rho kinase (ROCK) in the human trabecular meshwork (HTM). The HTM plays a crucial role in keeping the resistance to the outflow of aqueous humor, a pivotal element in maintaining a physiologically balanced IOP. An AAV vector, named GVB-2001, was specifically engineered to express a transgene to inhibit the activity of Rho kinase (ROCK) in the trabecular meshwork. Research-grade GVB-2001 was manufactured for proof-of-concept studies. In the in vitro part, ROCK activity, measured by ELISA, served as a metric to assess the efficacy of viral transduction in primary culture of human trabecular meshwork (HTM) cells. Various time points post-infection and multiple Multiplicity of Infection (MOI) values were systematically tested. For the in vivo segment, an ocular hypertensive rat model was induced by infecting rat eyes with Ad. hBMP2. This model was employed to investigate whether intracameral injection of GVB-2001 could effectively reduce IOP. Rats were euthanized two weeks post-AAV injection, and quantitative polymerase chain reaction (qPCR) was conducted to examine the biodistribution of GVB-2001 within ocular tissues. The transgene exhibited robust expression in HTM cells following viral infection, as illustrated in Figure 1A. Furthermore, AAV infection demonstrated a noteworthy and consistent reduction in ROCK activity within HTM cells across various time points and MOI levels, as depicted in Figures 1B and 1C. In the rat model, the IOP readings showed an increase following the injection of Ad. hBMP2, as illustrated in Figure 2A. Subsequently, a significant reduction in IOP was observed 7 days post-AAV injection, and this effect was sustained through day 14, as depicted in Figure 2B. Biodistribution analysis confirmed the exclusive detection of GVB-2001 in the trabecular meshwork (TM) of rat eyes, with no presence in the iris, retina, or cornea, as shown in Figure 2C. Ongoing investigations include dose-escalating efficacy studies and toxicity assessments. GVB-2001 was a robust gene therapy for glaucoma treatment, demonstrating its capacity to lower intraocular pressure (IOP) by effectively inhibiting Rho kinase (ROCK) activity in the trabecular meshwork. The proof-of-concept animal study lends substantial support to the viability of a gene therapy strategy, showcasing the potential for achieving a stable and enduring reduction in IOP with a singular intracameral injection.