Effective AAV-mediated gene replacement therapy in retinal organoids modeling AIPL1-associated LCA4

• Published in: Molecular therapy. Nucleic acids Vol. 35; no. 1; p. 102148
• Main Authors: Sai, Hali, Ollington, Bethany, Rezek, Farah O., Chai, Niuzheng, Lane, Amelia, Georgiadis, Anastasios, Bainbridge, James, Michaelides, Michel, Sacristan-Reviriego, Almudena, Perdigão, Pedro R.L., Leung, Amy, van der Spuy, Jacqueline
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.03.2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: adeno-associated virus; aryl hydrocarbon receptor interacting protein-like 1; gene therapy; induced pluripotent stem cells; inherited retinal degeneration; Leber congenital amaurosis; MT: Delivery strategies; Original; retinal organoid; retinal organoid; Leber congenital amaurosis; gene therapy; MT: Delivery strategies; adeno-associated virus; induced pluripotent stem cells; aryl hydrocarbon receptor interacting protein-like 1; inherited retinal degeneration
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2024.102148

Biallelic variations in the aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene cause Leber congenital amaurosis subtype 4 (LCA4), an autosomal recessive early-onset severe retinal dystrophy that leads to the rapid degeneration of retinal photoreceptors and the severe impairment of sight within the first few years of life. Currently, there is no treatment or cure for AIPL1-associated LCA4. In this study, we investigated the potential of adeno-associated virus-mediated AIPL1 gene replacement therapy in two previously validated human retinal organoid (RO) models of LCA4. We report here that photoreceptor-specific AIPL1 gene replacement therapy, currently being tested in a first-in-human application, effectively rescued molecular features of AIPL1-associated LCA4 in these models. Notably, the loss of retinal phosphodiesterase 6 was rescued and elevated cyclic guanosine monophosphate (cGMP) levels were reduced following treatment. Transcriptomic analysis of untreated and AAV-transduced ROs revealed transcriptomic changes in response to elevated cGMP levels and viral infection, respectively. Overall, this study supports AIPL1 gene therapy as a promising therapeutic intervention for LCA4. [Display omitted] In this study, van der Spuy and colleagues underscore the utility of RO models of retinal disease to interrogate therapeutic interventions. The authors report that gene replacement therapy in patient-derived or CRISPR-engineered ROs effectively rescued the molecular features of the severe inherited retinal degeneration, LCA4.