Calkins David J, Yu-Wai-Man Patrick, Newman Nancy J, Taiel Magali, Singh Pramila, Chalmey Clémentine, Rogue Alexandra, Carelli Valerio, Ancian Philippe, Sahel José A
Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA.
Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Mol Ther Methods Clin Dev. 2021 Oct 1;23:307-318. doi: 10.1016/j.omtm.2021.09.013. eCollection 2021 Dec 10.
Lenadogene nolparvovec (Lumevoq) gene therapy was developed to treat Leber hereditary optic neuropathy (LHON) caused by the m.11778G > A in 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 subunit protein. Lenadogene nolparvovec was administered by unilateral intravitreal injection in 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.
利纳多基因诺尔帕韦克（Lumevoq）基因疗法旨在治疗由线粒体呼吸链复合体I中的m.11778G＞A突变引起的Leber遗传性视神经病变（LHON）。利纳多基因诺尔帕韦克是一种复制缺陷型单链DNA重组腺相关病毒2型载体，包含一个编码人野生型亚基蛋白的密码子优化互补DNA。在两项随机、双盲、安慰剂对照的III期临床试验（REVERSE和RESCUE）中，对LHON患者进行了单侧玻璃体内注射利纳多基因诺尔帕韦克，结果视力得到了双侧改善。这些以及其他早期结果表明，利纳多基因诺尔帕韦克可能会从治疗眼转移至未治疗眼。为了进一步研究这种可能性，将利纳多基因诺尔帕韦克单侧注射到健康非人灵长类动物右眼的玻璃体中。注射后3个月和6个月时，在注射眼的所有眼组织和视神经组织中均可检测到病毒载体DNA，在对侧未注射眼的一些组织和视神经投射中也检测到较低水平的病毒载体DNA。结果表明，利纳多基因诺尔帕韦克可从注射眼转移至未注射眼，从而为LHON患者观察到的视力功能双侧改善提供了一种潜在解释。
