Leber hereditary optic neuropathy gene therapy.
AI Summary
Unilateral gene therapy for LHON unexpectedly improved vision bilaterally (up to 3 lines), but final visual acuity remained poor. This suggests some efficacy, but better strategies are needed for significant visual recovery.
Abstract
Purpose of review: To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON).
Recent findings: 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.
Summary
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.
MeSH Terms
Shields Classification
Key Concepts6
Results from G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy showed good safety.
Unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy in G11778A LHON Phase 3 randomized clinical trials resulted in unexpected bilateral partial improvements of BCVA, with mean logMAR BCVA improvements of up to nearly 0.3 logMAR (3 lines) in the treated eyes and approximately 0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes.
After gene therapy for G11778A LHON, final mean BCVA levels were in the range of approximately 1.3 logMAR (20/400) bilaterally.
Future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of 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 that the therapeutic window is narrowing before the onset of visual symptoms.
Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy hold 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.
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