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

Autor:	Sai H; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK., Ollington B; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK., Rezek FO; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK., Chai N; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK., Lane A; MeiraGTx, London N1 7NQ, UK., Georgiadis T; MeiraGTx, London N1 7NQ, UK., Bainbridge J; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.; NIHR Moorfields Biomedical Research Centre, London EC1V 2PD, UK., Michaelides M; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.; NIHR Moorfields Biomedical Research Centre, London EC1V 2PD, UK., Sacristan-Reviriego A; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.; Institute of Clinical Trials and Methodology, University College London, London WC1V 6LJ, UK., Perdigão PRL; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal., Leung A; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK., van der Spuy J; University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Feb 13; Vol. 35 (1), pp. 102148. Date of Electronic Publication: 2024 Feb 13 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102148
Abstrakt:	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. Competing Interests: A.Lane and T.G. are employees and stockholders of MeiraGTx. M.M. is a consultant and has equity in MeiraGTx. (© 2024 The Authors.)
Databáze:	MEDLINE
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