ArticleMolecular therapy. Methods & clinical development2015
Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss.
Article in Molecular therapy. Methods & clinical development, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Leber's Hereditary Optic Neuropathy as a Promising Disease for Gene Therapy Development.Advances in therapy · 2019Pooled it
- Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy.Brain : a journal of neurology · 2023Trial
- Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.Molecular psychiatry · 2026Review
- Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.Molecular biomedicine · 2026Review
- Oxidative stress imbalance and cellular damage mediated by the ND4 G11778A mutation.Scientific reports · 2026Article
- Advanced therapies for inherited optic neuropathies.Eye (London, England) · 2026Review
- Oxidative Stress and Inflammatory Biomarkers in Aqueous Humor and Blood of Patients with Leber's Hereditary Optic Neuropathy.Antioxidants (Basel, Switzerland) · 2025Article
- Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.Journal of translational medicine · 2025Review
- Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Leber's hereditary optic neuropathy: Update on the novel genes and therapeutic options.Journal of the Chinese Medical Association : JCMA · 2024Article
- Efficacy of Intravitreal rAAV2-ND4 Injection in Treated Versus Fellow Eyes with Leber's Hereditary Optic Neuropathy: A Meta-Analysis.Neuro-ophthalmology (Aeolus Press) · 2024Review
- Clinical Approaches for Mitochondrial Diseases.Cells · 2023Review
- Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.Cells · 2023Review
- Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?Antioxidants (Basel, Switzerland) · 2023Review
- AAV for Gene Therapy in Ocular Diseases: Progress and Prospects.Research (Washington, D.C.) · 2023Review
- Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.Frontiers in neuroscience · 2023Article
- Site-specific CRISPR-based mitochondrial DNA manipulation is limited by gRNA import.Scientific reports · 2022Article
- Leber Hereditary Optic Neuropathy: Molecular Pathophysiology and Updates on Gene Therapy.Biomedicines · 2022Review
- From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.Cold Spring Harbor perspectives in medicine · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.