Gene Therapy for MERTK-Associated Retinal Degenerations

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• MERTK-associated retinal degenerations involve impaired phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE).
• Rodent models exhibit similar phagocytic defects, making them valuable for studying these conditions.

Purpose of the Study:

• To evaluate the efficacy of subretinal injection of an RPE-specific adeno-associated virus serotype 2 (AAV2) vector, AAV2-VMD2-hMERTK, for long-term photoreceptor rescue.
• To assess the vector's impact on RPE phagocytosis and visual function in disease models.

Main Methods:

• Subretinal injection of AAV2-VMD2-hMERTK in RCS rats and Mertk-null mice.
• Assessment of photoreceptor survival and RPE phagocytosis.
• Measurement of electroretinogram (ERG) response amplitudes.

Main Results:

• Long-term photoreceptor rescue (up to 6.5 months) was observed in RCS rats following vector injection.
• Evidence of phagosomes in RPE cells in rescued regions of RCS retinas.
• Significant protective effects and increased ERG amplitudes in vector-injected eyes of Mertk-null mice.

Conclusions:

• The AAV2-VMD2-hMERTK vector effectively rescues photoreceptors and restores RPE phagocytosis in models of MERTK-associated retinal degeneration.
• These preclinical findings support the potential for favorable outcomes in upcoming clinical trials.