Abstract
Purpose :
The current standard of care for ocular hypertension associated with Glaucoma relies on daily eye drop medications to lower intraocular pressure (IOP), however, patient adherence is a major limitation. Intracameral gene therapy based on engineered microbial mechanosensitive channel (EMC) targeted to trabecular meshwork (TM) offers a novel approach to provide sustained IOP lowering through control of outflow facility. Here, we present measurement of aqueous humor (AH) outflow facility in IOP-elevated TGFb mouse model of glaucoma and evaluation of dose-dependent EMC gene therapy in enhancing outflow facility for IOP lowering.
Methods :
Intravitreal injection of Ad5.TGFβ-2 in adult C57BL/6J mice was used for IOP elevation. IOP was measured by TonoLab. Self-complementary AAV (scAAV) was used to deliver three different doses of EMC to TM upon intracameral injection. To determine changes in aqueous outflow facility due to EMC transduction of TM, AH outflow measurement was conducted in anesthetized mice. Outflow facility was determined by multiple flow rate infusion measured by manometry in EMC-treated and control groups.
Results :
Intracameral delivery of scAAV-EMC led to EMC expression in TM of IOP-elevated TGFb mouse model of glaucoma. Reduction of AH outflow observed in the IOP elevated TGFb model, which was reversed (close to the outflow rate in normal mice) upon EMC treatment. The outflow facilitation was dependent on the EMC dose and was statistically significant (p <0.05) as compared to control group. This correlated with sustained IOP lowering in TGFb-injected mice after scAAV-EMC injection.
Conclusions :
Targeting the TM cells with engineered microbial mechanosensitive channel enables sensing of elevated intraocular pressure and actuation of AH outflow through the conventional outflow pathway. Since glaucoma and ocular hypertension is associated with myriad of genetic mutations, EMC gene therapy provides a gene-agnostic gene therapy via a common convergent pathway of enhancing aqueous humor outflow facility to lower the elevated IOP in glaucomatous eyes.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.