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    LHON therapy: Excellent safety and potential visual benefits

    Paris—The intravitreal injection of a recombinant AAV2/2 vector with the wild-type ND4 gene may be a big step forward in treating patients with Leber’s hereditary optic neuropathy (LHON). In a study evaluating the technology in LHON patients, preliminary data over 15 patients at 48-week follow up showed visual acuity improvements in patients who received the well-tolerated vector within 2 years of the start of vision loss.

    During that same time frame, color vision, and visual field showed some improvement more specifically in patients with better baseline values.

    Related: Genetic mutation findings in Spanish retinitis pigmentosa

    LHON affects the optic nerve at the level of the retinal ganglion cells. Three types of mitochondrial DNA mutations are seen in 95% of the affected patients, i.e., ND4, ND1, and ND6. The first is the most severe and the most frequent of the three and leads to a defect in the complex 1 respiratory chain and degeneration of the retinal ganglion cells and optic nerve.

    The result is acute loss of the central vision that occurs bilaterally usually within 8 weeks for 50% of the patients. There currently is no treatment available that can significantly improve the vision, explained Jose Alain Sahel, MD, Professor of Ophthalmology at Pierre and Marie Curie University Medical School, Paris.

    Dr. Sahel and his colleagues started their search for a treatment 12 years ago when they began exploring AAV2-based gene therapy to restore the ND4 function. They created an animal model of LHON in which to transfer the ND4 gene.

    More: Gene therapy improves functional vision in Leber congenital amaurosis

    This approach, GS010 (AAV2/2-ND4), involved using a mitochondrial targeting sequence, a unique and proprietary technology which allows expression of mitochondrial proteins into the mitochondria to correct the genetic defect. By so doing, they showed that the protein was expressed and the phenotype corrected in mutant rats.

    Subsequent research projects showed a strong proof of concept in animals, in vitro validation in fibroblast cells from patients with LHON, the absence of toxicity in primates, and the evaluation of the safety and tolerability of the vector in a phase Ib/IIa, the first trial in humans.


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