Rod Outer Segment Development Influences AAV-Mediated Photoreceptor Transduction After Subretinal Injection

Area of Science:

• Ophthalmology
• Gene Therapy
• Molecular Biology

Background:

• Adeno-associated virus (AAV) vectors are primary tools for photoreceptor (PR) gene delivery.
• Challenges remain in achieving efficient AAV transduction for severe PR degenerations.
• Understanding PR transduction factors is crucial for optimizing gene therapy.

Purpose of the Study:

• Investigate host factors influencing AAV-mediated PR transduction.
• Determine the role of rod outer segments in AAV transduction efficiency.
• Explore differences in AAV transduction between neonatal and adult retinas.

Main Methods:

• Subretinal and intravitreal injections of AAV vectors in neonatal and adult mice.
• Analysis of AAV transduction patterns in wild-type and retinal degeneration 1 (rd1) mice.
• Correlation of PR differentiation and rod outer segment development with transduction efficiency.

Main Results:

• Rod outer segment development is critical for efficient AAV-mediated rod transduction.
• Subretinal AAV injection preference shifts from cones to rods as outer segments mature.
• Altered rod outer segment development reduces rod transduction and increases cone transduction.
• rd1 mice with degenerated outer segments show increased cone transduction.

Conclusions:

• Rod outer segments significantly modulate AAV transduction efficiency in photoreceptors.
• The developmental stage and integrity of rod outer segments impact gene therapy outcomes.
• Targeting rod outer segments or accounting for their status may improve AAV-based gene delivery for retinal diseases.