Novel AAV44.9-Based Vectors Display Exceptional Characteristics for Retinal Gene Therapy

Area of Science:

• Ophthalmology
• Gene Therapy
• Molecular Virology

Background:

• Inherited retinal diseases (IRDs) are primarily caused by mutations in photoreceptor (PR) genes.
• Effective gene therapy requires vectors that transduce large retinal areas and efficiently target foveal cones.

Purpose of the Study:

• To evaluate the retinal tropism and potency of a novel adeno-associated virus (AAV) capsid, AAV44.9, and its derivatives.
• To compare AAV44.9's performance against established AAV vectors for gene delivery to photoreceptors.

Main Methods:

• Subretinal injection (SRI) of AAV vectors in mouse and macaque models.
• Assessment of transduction efficiency, tropism, and functional restoration in a mouse model of IRD.
• Evaluation of AAV44.9 and AAV44.9(E531D) in targeting cone and rod photoreceptors, including foveal and parafoveal regions.

Main Results:

• AAV44.9 and AAV44.9(E531D) demonstrated higher retinal transduction efficiency than benchmark AAV5 and AAV8 vectors in mice.
• Highly efficient cone and rod transduction was observed in macaques following submacular and peripheral SRI.
• AAV44.9(E531D) achieved up to 98% foveal cone transduction with extrafoveal injection and restored retinal function in an IRD mouse model.

Conclusions:

• AAV44.9 and its derivative AAV44.9(E531D) are potent vectors for widespread retinal gene therapy.
• These novel capsids show promise for treating IRDs, particularly those benefiting from extensive retinal coverage and foveal cone targeting.