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Abstract #120264 Published in IGR 25-1
AAV-NDI1 Therapy Provides Significant Benefit to Murine and Cellular Models of Glaucoma
Millington-Ward S; Palfi A; Shortall C; Finnegan LK; Bargroff E; Post IJM; Maguire J; Irnaten M; O Brien C; Kenna PF; Chadderton N; Farrar GJInternational journal of molecular sciences 2024; 25:
Glaucoma, a leading cause of blindness, is a multifactorial condition that leads to progressive loss of retinal ganglion cells (RGCs) and vision. Therapeutic interventions based on reducing ocular hypertension are not always successful. Emerging features of glaucoma include mitochondrial dysfunction and oxidative stress. In the current study, NDI1-based gene therapy, which improves mitochondrial function and reduces reactive oxygen species, was delivered intraocularly via an adeno-associated viral vector (AAV). This AAV-NDI1 therapy protected RGCs from cell death in treated (1552.4 ± 994.0 RGCs/mm) versus control eyes (1184.4 ± 978.4 RGCs/mm, < 0.05) in aged DBA/2J mice, a murine model of glaucoma. The photonegative responses (PhNRs) of RGCs were also improved in treated (6.4 ± 3.3 µV) versus control eyes (5.0 ± 3.1 µV, < 0.05) in these mice. AAV-NDI1 also provided benefits in glaucomatous human lamina cribrosa (LC) cells by significantly increasing basal and maximal oxygen consumption rates and ATP production in these cells. Similarly, NDI1 therapy significantly protected HO-insulted primary porcine LC cells from oxidative stress. This study highlights the potential utility of NDI1 therapies and the benefits of improving mitochondrial function in the treatment of glaucoma.
The School of Genetics and Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, D02VF25 Dublin, Ireland.
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