Multilocus Mitochondrial Mutations Do Not Directly Affect the Efficacy of Gene Therapy for Leber Hereditary Optic Neuropathy

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Title Multilocus Mitochondrial Mutations Do Not Directly Affect the Efficacy of Gene Therapy for Leber Hereditary Optic Neuropathy
Creator Shuo Yang, Chen Chen, Jia-Jia Yuan, Shuai-Shuai Wang, Xing Wan, Heng He, Si-Qi Ma, Bin Li
Affiliation Department of Ophthalmology (SY, J-JY, S-SW, XW, HH, S-QM, BL), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Eye Center (SY), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; and Center of Genetic Diagnosis (CC), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Abstract Purpose: Clinical trials of gene therapy for Leber hereditary optic neuropathy (LHON) were conducted in 9 volunteers with the mitochondrial mutation, G11778A in ND4. The purpose of this study was to investigate whether multilocus mitochondrial mutations directly influence the efficacy of gene therapy for LHON. Methods: Nine volunteers with LHON participated in a clinical trial with intravitreal injection of an adenoviral vector expressing wild-type ND4. Patients were subsequently divided into 2 groups: according to the differences in therapy efficacy and based on improvements in visual acuity. Full mitochondrial DNA sequences of the 2 groups of patients were generated and compared using PubMed, PolyPhen, and PROVEAN. Furthermore, the association between the detected mutations and clinical effects of gene therapy was analyzed. Results: Best-corrected visual acuity (BCVA) significantly improved (≥0.3 log of minimum angle of resolution [logMAR]) in 7 patients 6 months after gene therapy, whereas there was no significant change in BCVA (<0.3 logMAR) of the remaining 2 patients. All 9 patients carried the G1178A mutation in addition to other nonsynonymous mutations. Among these mutations, some were predicted to be neutral and deleterious. Meanwhile, different mitochondrial mutations in the group in which treatment was ineffective, compared with those in responders, were at nucleotide positions 6569 (CO1; Patient 3), 9641 (CO3; Patient 3), and 4491 (ND2; Patient 5). Conclusions: Detection of the 3 primary mitochondrial mutations causing LHON is sufficient for screening before gene therapy; sequencing of the entire mitochondrial genome is unnecessary before treatment. Patients with LHON can respond to targeted gene therapy irrespective of additional multilocus mitochondrial mutations.
OCR Text Show
Publisher Lippincott, Williams & Wilkins
Date 2020-03
Type Text
Source Journal of Neuro-Ophthalmology, March 2020, Volume 40, Issue 1
Language eng
Rights Management © North American Neuro-Ophthalmology Society
Publication Type Journal Article
ARK ark:/87278/s68687s9
Setname ehsl_novel_jno
Date Created 2021-01-22
Date Modified 2021-05-06
ID 1653470
Reference URL https://collections.lib.utah.edu/ark:/87278/s68687s9