Absence of lenadogene nolparvovec DNA in a brain tumor biopsy from a patient in the REVERSE clinical study, a case report

• Type of Material: Article
• Authors: Nancy Newman, Emory University; Pia R Mendoza, Emory University; Matthew Schniederjan, Emory University; David J Calkins, Vanderbilt University; Patrick Yu-Wai-Man, University of Cambridge; Valerie Biousse, Emory University; Valérie Carelli, UOC Clin Neurol; Magali Taiel, GenSight Biologics; Francois Rugiero, Diamond Pharma Serv ProPharma Grp; Pramila Singh, Charles River Laboratories; Alexandra Rogue, Charles River Laboratories; José-Alain Sahel, Sorbonne Universite; Philippe Ancian, Charles River Laboratories
• Language: English
• Date: 2022-07-12
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12883-022-02787-y
• Title of Journal or Parent Work: BMC NEUROLOGY
• Volume: 22
• Issue: 1
• Start Page: 257
• End Page: 257
• Grant/Funding Information: The Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA, processed and performed brain tissue/tumor analyses with no funding from the sponsor of the study.; Charles River Laboratories, funded by GenSight Biologics, performed sample analyses.; NJN is supported in part by an ophthalmology department core grant from the NIH/NEI (P30 EY006360). PYWM is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK), and receives funding from Fight for Sight (UK), the Isaac Newton Trust (UK), Moorfields Eye Charity, the Addenbrooke’s Charitable Trust, the National Eye Research Centre (UK), the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. VC is supported by grants from the Italian Ministry of Health (RF-2018-12366703), the Italian Ministry of Research (20172T2MHH), and Telethon-Italy (GUP15016). VC is also supported by patients’ organizations MITOCON and IFOND, and patients’ donations. JAS is supported by the Agence Nationale de la Recherche within the Programme Investissements d’Avenir, Institut Hospitalo Universitaire FOReSIGHT [ANR-18-IAHU 0001] and LabEx LIFESENSES (ANR-10-LABX-65).; All authors contributed to interpretation of the data and writing of the manuscript without payment as part of a scientific collaboration.
• Keywords: qPCR assay; BIODISTRIBUTION; Neurosciences & Neurology; EXPRESSION; DOGS; Lenadogene nolparvovec; Case report; Leber hereditary optic neuropathy; Recombinant adeno-associated virus vector 2 serotype 2; MUTATIONS; Science & Technology; GENE-THERAPY; OUTCOMES; Life Sciences & Biomedicine; ND4; COMPLEX-I; Viral vector transduction; Clinical Neurology
• Research Categories: Health Sciences, Pathology

Abstract

Background: Leber Hereditary Optic Neuropathy (LHON) is a rare, maternally-inherited mitochondrial disease that primarily affects retinal ganglion cells (RGCs) and their axons in the optic nerve, leading to irreversible, bilateral severe vision loss. Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss from LHON caused by the most prevalent m.11778G > A mitochondrial DNA point mutation in the MT-ND4 gene. Lenadogene nolparvovec is a replication-defective recombinant adeno-associated virus vector 2 serotype 2 (AAV2/2), encoding the human wild-type MT-ND4 protein. Lenadogene nolparvovec was administered by intravitreal injection (IVT) in LHON patients harboring the m.11778G > A ND4 mutation in a clinical development program including one phase 1/2 study (REVEAL), three phase 3 pivotal studies (REVERSE, RESCUE, REFLECT), and one long-term follow-up study (RESTORE, the follow-up of REVERSE and RESCUE patients). Case presentation: A 67-year-old woman with MT-ND4 LHON, included in the REVERSE clinical study, received a unilateral IVT of lenadogene nolparvovec in the right eye and a sham injection in the left eye in May 2016, 11.4 months and 8.8 months after vision loss in her right and left eyes, respectively. The patient had a normal brain magnetic resonance imaging with contrast at the time of diagnosis of LHON. Two years after treatment administration, BCVA had improved in both eyes. The product was well tolerated with mild and resolutive anterior chamber inflammation in the treated eye. In May 2019, the patient was diagnosed with a right temporal lobe glioblastoma, IDH-wildtype, World Health Organization grade 4, based on histological analysis of a tumor excision. The brain tumor was assessed for the presence of vector DNA by using a sensitive validated qPCR assay targeting the ND4 sequence of the vector. Conclusion: ND4 DNA was not detected (below 15.625 copies/μg of genomic DNA) in DNA extracted from the brain tumor, while a housekeeping gene DNA was detected at high levels. Taken together, this data shows the absence of detection of lenadogene nolparvovec in a brain tumor (glioblastoma) of a treated patient in the REVERSE clinical trial 3 years after gene therapy administration, supporting the long-term favorable safety of lenadogene nolparvovec.