June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Pharmacokinetic and Safety Analyses of rAAV8.BMI1 in C57BL/6 mice
Author Affiliations & Notes
  • Zhongyang Lu
    Oculogenex Inc., Torrance, California, United States
  • Sibley Bardales
    Oculogenex Inc., Torrance, California, United States
  • Christina Kim
    Oculogenex Inc., Torrance, California, United States
  • Gary Mansfield
    Oculogenex Inc., Torrance, California, United States
  • Hema Ramkumar
    Oculogenex Inc., Torrance, California, United States
  • Footnotes
    Commercial Relationships   Zhongyang Lu None; Sibley Bardales None; Christina Kim None; Gary Mansfield None; Hema Ramkumar None
  • Footnotes
    Support  NSF Phase II Award 2208096, CASIS Grant GA-2021-8545
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1137. doi:
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    • Get Citation

      Zhongyang Lu, Sibley Bardales, Christina Kim, Gary Mansfield, Hema Ramkumar; Pharmacokinetic and Safety Analyses of rAAV8.BMI1 in C57BL/6 mice. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1137.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The BMI1 gene encodes a polycomb ring finger protein that is important in the self-renewal of retinal progenitor cells and is an epigenetic repressor of regulatory genes involved in the self-renewal and DNA damage repair of somatic cells. A vector rAAV8.BMI1 has been designed to deliver the BMI1 protein to the retina for the treatment of retinal degenerations. In this study, we evaluated the safety and tolerability of subretinal rAAV8.BMI1 after one month in a rodent model.

Methods : Thirty 12-week-old C57BL//6 mice were treated bilaterally with subretinal rAAV8.Stuffer (n=10), rAAV8.BMI1 8*107 viral genomes/eye (n=10), and rAAV8.BMI1 6*109 viral genomes/eye (n=10). Electroretinography (ERG), optical coherence tomography (OCT) retinal imaging, histopathology, and RPE and retinal tissue analyses were performed. Bmi1 levels were quantified using an ELISA, and statistical analyses were performed using GraphPad Prism software. Data were expressed as mean ± SD and analyzed using one-way ANOVA.

Results : There was a significant increase in RPE BMI1 (ng/ml) from 1.57±1.67 to 3.72±2.3 in the 8*107 vg/eye and to 5.35±3.21 in the 6*109 vg/eye (p<0.01). There was a significant increase in retinal BMI1 (ng/ml) from 7.14±1.5 to 13.21±7.9 in the 6*109 vg/eye (p<0.01). Though subretinal injection usually decreases ERG amplitudes, we found a significant increase in ERG a and c wave amplitudes after subretinal injection of 8*107 vg/eye of rAAV8.Bmi1 (p<0.05 and p<0.01 respectively).

Conclusions : rAAV8.BMI1 is well-tolerated in rodents based on OCT and ERG. BMI1 levels were increased in RPE and Retina, indicating this designed rAAV can increase BMI1 levels and can be further evaluated for the treatment of retinal degenerations.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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