Retinal BMI1 Expression Preserves Photoreceptors in Sodium-Iodate-Induced Oxidative Stress Models

Area of Science:

• Ophthalmology
• Gene Therapy
• Molecular Biology

Background:

• Dry age-related macular degeneration (AMD) is a major cause of vision loss with no current treatments for early/intermediate stages.
• Oxidative stress drives retinal degeneration in AMD, making sodium iodate (NaIO3)-induced injury a relevant preclinical model.
• BMI1, a protein involved in DNA repair and cellular renewal, is a potential therapeutic target for neuroprotection in the retina.

Purpose of the Study:

• To evaluate the efficacy of adeno-associated virus (AAV)-mediated BMI1 gene delivery via subretinal (SR) and suprachoroidal (SC) routes in preclinical models of dry AMD.
• To assess the safety and expression levels of BMI1 following gene delivery.
• To determine the protective effects of BMI1 gene therapy on retinal structure and function after oxidative injury.

Main Methods:

• AAV5.BMI1 delivered SR and AAV8.BMI1 delivered SC in mouse models.
• Sodium iodate (NaIO3) induced oxidative injury to mimic AMD.
• Evaluations included optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays.
• Safety and toxicity were assessed post-injection.

Main Results:

• Suprachoroidal delivery of AAV8.BMI1 resulted in high retinal BMI1 expression without toxicity.
• Treated eyes demonstrated dose-dependent preservation of outer nuclear layer (ONL) thickness.
• Significantly improved electroretinography (ERG) responses indicated structural and functional protection.

Conclusions:

• Suprachoroidal AAV.BMI1 gene therapy is a safe and effective approach for protecting the retina from oxidative damage.
• This minimally invasive gene therapy strategy shows potential for treating intermediate dry AMD.
• Further development of SC AAV.BMI1 gene therapy is warranted for early AMD intervention.