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

Sai, Hali; Ollington, Bethany; Rezek, Farah O; Chai, Niuzheng; Lane, Amelia; Georgiadis, Tassos; Bainbridge, James; ... van der Spuy, Jacqueline; + view all (2024) Effective AAV-mediated gene replacement therapy in retinal organoids modelling AIPL1-associated LCA4. Molecular Therapy - Nucleic Acids , 35 (1) , Article 102148. 10.1016/j.omtn.2024.102148. Green open access

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Abstract

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.

Type: Article
Title: Effective AAV-mediated gene replacement therapy in retinal organoids modelling AIPL1-associated LCA4
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtn.2024.102148
Publisher version: http://dx.doi.org/10.1016/j.omtn.2024.102148
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: MT: Delivery strategies, Leber congenital amaurosis, retinal organoid, aryl hydrocarbon receptor, interacting protein-like 1adeno-associated virus, inherited retinal degeneration, gene therapy, induced pluripotent stem cells
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10188446
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