Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy

Vignal, Catherine; Uretsky, Scott; Fitoussi, Serge; Galy, Anne; Blouin, Laure; Girmens, Jean François; Bidot, Samuel; Thomasson, Nitza; Bouquet, Céline; Valero, Sonia; Meunier, Sandrine; Combal, Jean Philippe; Gilly, Bernard; Katz, Barrett; Sahel, J

doi:10.1016/j.ophtha.2017.12.036

Cited by 89 publications

(81 citation statements)

References 6 publications

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“…Hence, in primates, the thicker ILM at the vitreo-retinal interphase limits the transduction of cells to a small parafoveal ring even after the injection of novel, mutant capsids with improved cellular transduction in rodents. 56,57 Intravitreal injection of vector is thus currently limited to clinical trials that target diseases that affect the inner retina, such as Leber hereditary optic neuropathy, 47,49,50 and diseases such as X-linked retinoschisis where the retinal architecture is affected by the causative mutation. 48 Additionally, in X-linked retinoschisis, the disease state arguably breaks down the interphase barriers to some extent, allowing for better vector penetration.…”

Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

MacDonald

Moen²,

Duncan

et al. 2020

Trans. Vis. Sci. Tech.

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Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

MacDonald

Moen²,

Duncan

et al. 2020

Trans. Vis. Sci. Tech.

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“…The most common ocular adverse event related to treatment was intraocular inflammation and IOP elevation, with all ocular adverse events resolving after treatment. Although the study was not designed to evaluate the efficacy of the vector, a significant improvement of BCVA was noted in 6/15 patients …”

Section: Ocular Diseases Targeted By Aav Gene Therapy In Humansmentioning

confidence: 99%

“…Although the study was not designed to evaluate the efficacy of the vector, a significant improvement of BCVA was noted in 6/15 patients. 89 GenSight Biologics subsequently initiated phase III clinical trials. The REVERSE trial (NCT02652780) enrolled patients with ND4 mutations who have had vision loss for 7 mo to 1 y, while the RESCUE trial (NCT02652767) enrolled patients with vision loss present for 6 mo or less.…”

Section: X-linked Retinoschisismentioning

confidence: 99%

Gene therapy and the adeno‐associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations

Ramlogan‐Steel

Murali

Andrzejewski

et al. 2019

Clinical Exper Ophthalmology

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Voretigene neparvovec‐rzyl was recently approved for the treatment of Leber congenital amaurosis, and the use of gene therapy for eye disease is attracting even greater interest. The eye has immune privileged status, is easily accessible, requires a reduced dosage of therapy due to its size and is highly compartmentalized, significantly reducing systemic spread. Adeno‐associated virus (AAV), with its low pathogenicity, prolonged expression profile and ability to transduce multiple cell types, has become the leading gene therapy vector. Target diseases have moved beyond currently untreatable inherited dystrophies to common, partially treatable acquired conditions such as exudative age‐related macular degeneration and glaucoma, but use of the technology in these conditions imposes added obligations for caution in vector design. This review discusses the current status of AAV gene therapy trials in genetic and acquired ocular diseases, and explores new scientific developments, which could help ensure effective and safe use of the therapy in the future.

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“…Significant advances are also being made for optic neuropathies and clinical trials are currently being conducted to evaluate the efficacy of GS010, an AAV2 construct containing the human wild-type NADH dehydrogenase subunit 4 (ND4) gene to treat patients with Leber's Hereditary Optic Neuropathy due to the G11778A ND4 mitochondrial mutation. 62,63 Preliminary data from the Phase I/II trial showed promising results (NCT02064569) and provided the foundation for two Phase III clinical trials which are currently underway (NCT02652780, NCT02652767). Clinically meaningful functional improvement has recently been reported with 72-week data from the REVERSE Phase III clinical trial (NCT02652780) which demonstrates that 45.9% of treated eyes achieved a significant improvement of 0.3 LogCS or more compared to 24.9% improvement seen in sham-treated eyes (p-0.0047).…”

Section: Gene Therapymentioning

confidence: 99%

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

Khatib

Martin

2019

Current Eye Research

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Purpose: The eye is currently at the forefront of translational medicine and therapeutics. However, despite advances in technology, primary open-angle glaucoma remains the leading cause of irreversible blindness worldwide. Traditional intraocular pressure (IOP)-lowering therapies are often not sufficient to prevent progression to blindness, even in patients with access to high-quality healthcare. Neuroprotection strategies, which aim to boost the ability of target cells to withstand a pathological insult, have shown significant promise in animal models but none have shown clinically relevant efficacy in human clinical trials to date. We sought to evaluate the current status of neuroprotection clinical trials for glaucoma and identify limitations which have prevented translation of new glaucoma therapies to date. Methods: Literature searches identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library and Web of Science databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings and conference proceedings, and clinical trial registries. Results: We discuss six key neuroprotective strategies for glaucoma that have reached the clinical trial stage. Delivery of neurotrophic factors through gene therapy is also progressing towards glaucoma clinical trials. Refinements in trial design and the use of new modalities to define structural and functional endpoints may improve our assessment of disease activity and treatment efficacy. Advances in our understanding of compartmentalised glaucomatous degeneration and continued progress in the molecular profiling of glaucoma patients will enable us to predict individual risk and tailor treatment. Conclusion: New approaches to future glaucoma neuroprotection trials could improve the prospects for new glaucoma therapies. Glaucoma treatment tailored according to an individual's unique risk profile may become increasingly common in the future. ARTICLE HISTORY

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Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy

Cited by 89 publications

References 6 publications

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

Gene therapy and the adeno‐associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

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