Abstract
Purpose :
The BMI1 gene is ubiquitously expressed in the mouse retina and is a cytoprotective regulatory gene involved in the self-renewal and DNA damage repair of somatic cells, including the retina. A vector AAV8.BMI1 has been optimized to deliver the BMI1 protein to the retina and retinal pigment epithelium (RPE) for the treatment of dry age-related macular degeneration (AMD). The suprachoroidal space has been demonstrated to be a safe and effective route of administration for targeted drug delivery for macular diseases. In this study, we evaluated the safety and tolerability of suprachoroidal delivery of rAAV8.BMI1 in mouse model.
Methods :
Thirty 12-week-old C57B/6 mice were treated bilaterally with subretinal rAAV8.Stuffer 1x1010, rAAV8.BMI1 5x109 viral genomes/eye, and rAAV8.BMI1 1x1010 viral genomes/eye. Electroretinography (ERG), optical coherence tomography (OCT) retinal imaging, histopathology, and RPE and retinal tissue analyses were performed. BMI1 levels were quantified using an MSD assay, and statistical analyses were performed using GraphPad Prism software. Data were expressed as mean ± SEM and analyzed using one-way ANOVA.
Results :
There was a significant increase in RPE BMI1 (ng/mg) from 305.8±20.8 to 1091.9±390.3 and in retina from 963.6±28.2 to 1540.9±265.0 in the 1x1010 vg/eye (p<0.001) compared to control mice. There were no significant differences in ERG a, b and c wave amplitudes and retinal structure after suprachoroidal injection between treatment groups. Overexpression of BMI1 had no off-target effects in the rodent eye.
Conclusions :
These findings further support the importance of suprachoroidal injection as an effective route of administration for gene therapy in mice and demonstrate the ability to directly deliver the vector to RPE and photoreceptors. BMI1 levels were Increased in RPE and retina, indicating this designed AAV8 can stably increase BMI1 levels and can be further evaluated the treatment for retinal degenerations such as dry AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.