Retinal gene therapy using epiretinal AAV-containing fibrin hydrogel implants

Area of Science:

• Ophthalmology
• Gene Therapy
• Biomaterials

Background:

• Subretinal injection of adeno-associated virus (AAV) is a common route for retinal gene therapy but can cause adverse events like chorioretinal atrophy.
• Current subretinal delivery methods often result in localized transduction, limiting therapeutic efficacy.
• Intravitreal injections, while less invasive, typically lead to insufficient transduction and inflammation.

Purpose of the Study:

• To develop and evaluate a novel epiretinal hydrogel delivery system for AAV gene therapy.
• To compare the efficacy and safety of epiretinal hydrogel delivery with traditional subretinal and intravitreal injection methods.
• To assess the potential of this new technology for treating retinal degenerations.

Main Methods:

• High-concentration fibrin hydrogels were manufactured to encapsulate adeno-associated virus serotype 2 carrying the green fluorescent protein (AAV2-GFP).
• The hydrogels were characterized for AAV distribution, mechanical properties, and infectivity.
• Epiretinal, subretinal, and intravitreal placements of AAV2-GFP were performed in animal models (n=11, n=5, and n=3, respectively).

Main Results:

• Subretinal injection resulted in inconsistent retinal pigment epithelium (RPE) transduction, localized delivery, and severe atrophy in two cases.
• Intravitreal injection showed weak transduction and induced inflammation.
• Epiretinal hydrogels degraded within days, achieving broad RPE transduction without observable atrophy or inflammation.

Conclusions:

• Epiretinal placement of fibrin-AAV hydrogels provides a promising alternative for retinal gene therapy delivery.
• This method overcomes the limitations of subretinal and intravitreal injections, offering improved safety and efficacy.
• The technology holds potential for advancing treatments for various ocular and systemic diseases.