title: Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.
abstract: Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2-9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the contralateral eye after intravitreal injections. No serious safety problem was observed in the 3-year follow-up of the 9 participants enrolled in this virus-based gene therapy. Meanwhile, our results support the use of intravitreal rAAV2-ND4 as an aggressive maneuver in our clinical trial. Further study in additional patients and in these 9 subjects is needed to better understand the effects of rAAV2-ND4 gene therapy on LHON and to increase the applications of this technique.
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Si-Qi
authors.initials: SQ
authors.lastname: Ma
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Oncology, Central Hospital, Ezhou City, People's Republic of China.
authors.forename: Min-Jian
authors.initials: MJ
authors.lastname: Zhao
authors.affiliation: Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Dao-Wen
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Beijing FivePlus Molecular Medicine Institute Co. Ltd., Beijing, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dong
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Yuan
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Wuhan Phoebus Biological Technology Limited Company, Wuhan, People's Republic of China. Electronic address: libin-12@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D000229:Dependovirus / Q000235:genetics; D005074:Evoked Potentials, Visual; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity; D014794:Visual Fields; D055815:Young Adult
chemical_list: C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
keywords: Best-corrected visual acuity; Gene therapy; Leber's hereditary optic neuropathy