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Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and hi...

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Autores principales: Daich Varela, Malena, Cabral de Guimaraes, Thales Antonio, Georgiou, Michalis, Michaelides, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961750/
https://www.ncbi.nlm.nih.gov/pubmed/33712480
http://dx.doi.org/10.1136/bjophthalmol-2020-318483
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author Daich Varela, Malena
Cabral de Guimaraes, Thales Antonio
Georgiou, Michalis
Michaelides, Michel
author_facet Daich Varela, Malena
Cabral de Guimaraes, Thales Antonio
Georgiou, Michalis
Michaelides, Michel
author_sort Daich Varela, Malena
collection PubMed
description Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.
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spelling pubmed-89617502022-04-11 Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials Daich Varela, Malena Cabral de Guimaraes, Thales Antonio Georgiou, Michalis Michaelides, Michel Br J Ophthalmol Review Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation. BMJ Publishing Group 2022-04 2021-03-12 /pmc/articles/PMC8961750/ /pubmed/33712480 http://dx.doi.org/10.1136/bjophthalmol-2020-318483 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
spellingShingle Review
Daich Varela, Malena
Cabral de Guimaraes, Thales Antonio
Georgiou, Michalis
Michaelides, Michel
Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title_full Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title_fullStr Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title_full_unstemmed Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title_short Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
title_sort leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961750/
https://www.ncbi.nlm.nih.gov/pubmed/33712480
http://dx.doi.org/10.1136/bjophthalmol-2020-318483
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