Leber hereditary optic neuropathy gene therapy.
Journal
Current opinion in ophthalmology
ISSN: 1531-7021
Titre abrégé: Curr Opin Ophthalmol
Pays: United States
ID NLM: 9011108
Informations de publication
Date de publication:
21 Dec 2023
21 Dec 2023
Historique:
medline:
20
12
2023
pubmed:
20
12
2023
entrez:
20
12
2023
Statut:
aheadofprint
Résumé
To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON). Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally. Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops.
Identifiants
pubmed: 38117686
doi: 10.1097/ICU.0000000000001028
pii: 00055735-990000000-00144
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
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