Preclinical evaluation of ALDH1A1 gene therapy for the prevention of diabetic retinopathy

Abstract

This study aimed to evaluate the effectiveness of ALDH1a1 gene therapy in preventing diabetic retinopathy (DR), a neurovascular condition caused by diabetes and the toxic lipid aldehyde acrolein (ACR). The role of ALDH1a1 in detoxifying ACR was assessed both in vitro and in vivo. To model Müller cell dysfunction in DR, QMMuC-1 murine Müller cells were exposed to varying doses of ACR. The effects of ACR on inflammatory gene expression and markers of Müller cell dysfunction were measured, along with the potential of AAV2.ALDH1A1 therapy to prevent ACR-induced damage. In vivo, male Sprague-Dawley rats were divided into four groups: nondiabetic, streptozotocin (STZ)-induced diabetic, and STZ-induced diabetic rats treated with either control virus (AAV2.eGFP) or AAV2.ALDH1A1. ACR significantly impacted Müller cells, with high concentrations inhibiting cell proliferation and causing cell death, while lower concentrations led to FDP-lysine accumulation and increased inflammatory cytokine expression. These effects were accompanied by elevated oxidative stress markers and reduced expression of neurotrophic factors. AAV2.ALDH1a1 treatment successfully prevented ACR-induced alterations in vitro. In diabetic rats, AAV2.ALDH1a1 increased ALDH1a1 protein expression and reduced neurodegenerative and other pathological changes. Exposure of QMMuC-1 cells to ACR mirrored the cellular damage observed in Müller cells in the diabetic retina. Overall, this research suggests that ALDH1a1 gene therapy may be a promising strategy to prevent ACR-induced Müller cell dysfunction and neurodegeneration in diabetes.

Thesis is embargoed until 31st December 2027.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Republic of Türkiye Ministry of National Education
Supervisor	Tim Curtis (Supervisor), Alan Stitt (Supervisor) & Mei Chen (Supervisor)