Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates

David J Calkins,Patrick Yu-Wai-Man,Nancy J Newman,Magali Taiel,Pramila Singh,Clémentine Chalmey,Alexandra Rogue,Valerio Carelli,Philippe Ancian,José A Sahel

doi:10.1016/j.omtm.2021.09.013

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.

Highlights

Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss due to Leber hereditary optic neuropathy (LHON) caused by the most common m.11778G > A mutation affecting the nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase subunit 4 (MT-ND4) gene
Tonometry values for intraocular pressure (IOP) of the injected eye were above the normal range in some treated (4 of 6) and control (1 of 2) animals immediately after IVT administration and rapidly came back to normal range
In four separate clinical trials, including one phase 1/2 study (REVEAL), two pivotal trials (REVERSE and RESCUE), and one long-term follow-up study (RESTORE), MT-ND4 LHON patients unilaterally injected with lenadogene nolparvovec demonstrated bilateral visual improvement beyond the expectations of the natural history of the disease.[8,9,10,11,17,18,19]

Summary

Introduction

Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss due to Leber hereditary optic neuropathy (LHON) caused by the most common m.11778G > A mutation affecting the nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase (complex I) subunit 4 (MT-ND4) gene. The construct includes the cis-acting elements of human cytochrome c oxidase 10 (COX10) mitochondrial ribonucleic acid (mtRNA), ensuring efficient delivery of the corresponding hybrid mRNA to the mitochondrial surface and the translocation of the translated human ND4 protein into the mitochondria. This allotopic expression strategy efficiently complements the mtDNA mutation in cell and animal models, allowing rescue of the mitochondrial respiratory chain defect and improved RGC survival.[1,2,3,4,5,6,7]

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