ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Ocular stress enhances contralateral transfer of lenadogene nolparvovec gene therapy through astrocyte networks.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 13 citations in OpenAlex.
- Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.JAMA ophthalmology · 2025Trial
- First pilot study of intrastromal rAAV-PAX6 gene therapy suggests improved corneal thickness and transcription correction in aniridic mouse.Molecular therapy. Advances · 2026Article
- Update on the Management of ABCA4 Retinopathy (Stargardt Disease).Ophthalmology and therapy · 2026Review
- Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.Journal of translational medicine · 2025Review
- Bilateral retinal rescue through unilateral AAV8-CYP4V2 gene delivery in Bietti crystalline dystrophy.Molecular therapy. Methods & clinical development · 2025Article
- Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial.EClinicalMedicine · 2025Article
- Preclinical studies of an AAV8-CYP4V2 gene therapy VGR-R01 for the treatment of Bietti crystalline dystrophy.Molecular therapy. Methods & clinical development · 2025Article
- Bilateral astrocyte reaction to unilateral insult in the optic projection to the brain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Mechanisms of Neuroprotection by Topical Rho Kinase Inhibition in Experimental Mouse Glaucoma and Optic Neuropathy.Investigative ophthalmology & visual science · 2024Article
- Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy.Cold Spring Harbor perspectives in medicine · 2024Review
- Clinical Approaches for Mitochondrial Diseases.Cells · 2023Review
- RGC-specific ATF4 and/or CHOP deletion rescues glaucomatous neurodegeneration and visual function.Molecular therapy. Nucleic acids · 2023Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Lenadogene nolparvovec (GS010) was developed to treat a point mutation in mitochondrial ND4 that causes Leber hereditary optic neuropathy. GS010 delivers human cDNA encoding wild-type ND4 packaged into an rAAV2/2 vector that transduces retinal ganglion cells, to induce allotopic expression of hybrid mitochondrial ND4. GS010 clinical trials improved best-corrected visual acuity (BCVA) up to 5 years after treatment. Interestingly, unilateral treatment improved BCVA bilaterally. Subsequent studies revealed GS010 DNA in visual tissues contralateral to the injected eye, suggesting migration. Here we tested whether unilateral intraocular pressure (IOP) elevation could influence the transfer of viral ND4 RNA in contralateral tissues after GS010 delivery to the IOP-elevated eye and probed a potential mechanism mediating translocation in mice. We found IOP elevation enhanced viral ND4 RNA transcripts in contralateral visual tissues, including retinas. Using conditional transgenic mice, we depleted astrocytic gap junction connexin 43 (Cx43), required for distant redistribution of metabolic resources between astrocytes during stress. After unilateral IOP elevation and GS010 injection, Cx43 knockdown eradicated ND4 RNA transcript detection in contralateral retinal tissues, while transcript was still detectable in optic nerves. Overall, our study indicates long-range migration of GS010 product to contralateral visual tissues is enhanced by Cx43-linked astrocyte networks.
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Registered trials
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