Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates

• Type of Material: Article
• Authors: David J Calkins, Vanderbilt University; Patrick Yu-Wai-Man, University of Cambridge; Nancy Newman, Emory University; Magali Taiel, GenSight Biologics; Pramila Singh, Charles River Laboratories; Clémentine Chalmey, Charles River Laboratories; Alexandra Rogue, Charles River Laboratories; Valerio Carelli, IRCCS Istituto delle Scienze Neurologiche di Bologna; Philippe Ancian, Charles River Laboratories; José A Sahel, Sorbonne Universite
• Language: English
• Date: 2021-12-10
• Publisher: CELL PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2021.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.omtm.2021.09.013
• Title of Journal or Parent Work: MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
• Volume: 23
• Start Page: 307
• End Page: 318
• Keywords: Life Sciences & Biomedicine; MUTATIONS; HEREDITARY OPTIC NEUROPATHY; ASTROCYTES; OUTCOMES; Research & Experimental Medicine; MITOCHONDRIAL BIOGENESIS; BEVACIZUMAB INJECTION; EXPRESSION; Medicine, Research & Experimental; Science & Technology; COMPLEX-I; EYE
• Research Categories: Engineering, Biomedical; Health Sciences, Opthamology

Abstract

Lenadogene nolparvovec (Lumevoq) gene therapy was developed to treat Leber hereditary optic neuropathy (LHON) caused by the m.11778G > A in MT-ND4 that affects complex I of the mitochondrial respiratory chain. Lenadogene nolparvovec is a replication-defective, single-stranded DNA recombinant adeno-associated virus vector 2 serotype 2, containing a codon-optimized complementary DNA encoding the human wild-type MT-ND4 subunit protein. Lenadogene nolparvovec was administered by unilateral intravitreal injection in MT-ND4 LHON patients in two randomized, double-masked, and sham-controlled phase III clinical trials (REVERSE and RESCUE), resulting in bilateral improvement of visual acuity. These and other earlier results suggest that lenadogene nolparvovec may travel from the treated to the untreated eye. To investigate this possibility further, lenadogene nolparvovec was unilaterally injected into the vitreous body of the right eye of healthy, nonhuman primates. Viral vector DNA was quantifiable in all eye and optic nerve tissues of the injected eye and was detected at lower levels in some tissues of the contralateral, noninjected eye, and optic projections, at 3 and 6 months after injection. The results suggest that lenadogene nolparvovec transfers from the injected to the noninjected eye, thus providing a potential explanation for the bilateral improvement of visual function observed in the LHON patients.