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Importance: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON)., Objective: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration., Design, Setting, and Participants: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye., Intervention: Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies., Main Outcomes and Measures: Measures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events., Results: Among the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was -0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (-0 line) in gene therapy-treated and sham eyes, respectively (difference, -0.03; 95% CI, -0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of -0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and -0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, -0.05; 95% CI, -0.15 to 0.04; P = .27). An improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham., Conclusions and Relevance: In this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03406104.

Background: Investing in late-stage clinical trials, trial sites, and production capacity for new health products could improve access to vaccines, therapeutics, and infectious disease diagnostics in middle-income countries. This study assesses the case for such investment in three of these countries: India, Kenya, and South Africa., Methods: We applied investment case modelling and assessed how many cases, deaths, and disability-adjusted life years (DALYs) could be averted from the development and manufacturing of new technologies (therapeutics and vaccines) in these countries from 2021 to 2036, for five diseases-HIV, tuberculosis, malaria, pneumonia, and diarrhoeal diseases. We also estimated the economic benefits that might accrue from making these investments and we developed benefit-cost ratios for each of the three middle-income countries. Our modelling applies two investment case perspectives: a societal perspective with all costs and benefits measured at the societal level, and a country perspective to estimate how much health and economic benefit accrues to each middle-income country for every dollar invested in clinical trials and manufacturing by the middle-income country government. For each perspective, we modelled two scenarios: one that considers only domestic health and economic benefits; and one that includes regional health and economic benefits. In the regional scenarios, we assumed that new products developed and manufactured in India would benefit eight countries in south Asia, whereas new products developed and manufactured in Kenya would benefit all 21 countries in the Common Market for Eastern and Southern Africa (COMESA). We also assumed that all 16 countries in the Southern African Development Community (SADC) would benefit from products developed and manufactured in South Africa., Findings: From 2021 to 2036, product development and manufacturing in Kenya could avert 4·44 million deaths and 206·27 million DALYs in the COMESA region. In South Africa, it could prevent 5·19 million deaths and 253·83 million DALYs in the SADC region. In India, it could avert 9·76 million deaths and 374·42 million DALYs in south Asia. Economic returns would be especially high if new tools were produced for regional markets rather than for domestic markets only. Under a societal perspective, regional returns outweigh investments by a factor of 20·51 in Kenya, 33·27 in South Africa, and 66·56 in India. Under a country perspective, the regional benefit-cost ratios amount to 60·71 in India, 8·78 in Kenya, and 11·88 in South Africa., Interpretation: Our study supports the creation of regional hubs for clinical trials and product manufacturing compared with narrow national efforts., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests All authors report grants from the Bill & Melinda Gates Foundation during the conduct of the study. RK also serves as chairman of the steering committee of the Coalition for Health Research & Development, a policy and advocacy coalition that is funded by the Bill & Melinda Gates Foundation. This is a voluntary position that does not have any direct renumeration., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues., Cases Presentation: The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI., Discussion: Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity., Conclusion: The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials., Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25)., Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline., Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)