Seven-Year Follow-up of Gene Therapy for Leber’s Hereditary Optic Neuropathy
Authors: Jiajia Yuan, Yong Zhang, Hongli Liu, Dan Wang, Yangyang Du, Zhen Tian, Xin Li, Shuo Yang, Han Pei, Xing Wan, Su Xiao, Lin Song, Xiao Xiao, Jian Sun, Zhitao Wang, Bin Li
Journal: Ophthalmology (2020)

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial mutation with simultaneous or consecutive binocular painless loss of vision and central visual field (VF) defects.1Lam B.L. Feuer W.J. Schiffman J.C. et al.Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial.JAMA Ophthalmol. 2014; 132: 428-436Crossref PubMed Scopus (77) Google Scholar In 2008, we initiated recombinant adeno-associated virus-mediated gene therapy research for LHON. Between 2011 and 2012, we evaluated the efficacy, durability, and long-term safety in 9 patients with the LHON mt11778G→A mutation (ClinicalTrials.gov identifier, NCT01267422). Except for patient 1, all patients received a single intravitreal injection of gene therapy agent. The eye with worse visual acuity was selected as the injection eye, and the right eye was selected for treatment if visual acuity was the same in both eyes. The results from the 9 treated patients at 36 months of follow-up after gene therapy treatment have been published previously.2Yang S. Ma S.Q. Wan X. et al.Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.EBioMedicine. 2016; 10: 258-268Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar In this report, the results for 8 of 9 treated patients who completed the 75- to 90-month posttreatment follow-up are presented. The study protocol was reviewed and approved by the independent ethics committee and institutional review board at Ezhou Center Hospital. Written informed consent was obtained from all patients before their participation in the study. The study was conducted in accordance with the tenets of the Declaration of Helsinki. Details of study design (ClinicalTrials.gov identifier, NCT01267422), informed consent, and vector administration have been published previously.2Yang S. Ma S.Q. Wan X. et al.Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.EBioMedicine. 2016; 10: 258-268Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Eight of 9 treated patients were followed up for up to 75 to 90 months with complete ophthalmic and general systems evaluation except for patient 8. Patient 8 did not return for the long-term observation period of 7 years after gene therapy; only the examination results at 36 months after treatment were available. However, we were able to conduct a telephone follow-up collecting information about his general physical condition. At each follow-up visit, patients underwent a systemic examination, including general physical examination with routine blood and urine analysis, electrocardiography, and chest radiography, in addition to the ophthalmic examination. The primary and secondary end points were defined as the change in best-corrected visual acuity (BCVA) and VF, respectively. All examinations before and after surgery were conducted by the same technicians (L.S., X.X., J.S., Z.W.) in the Department Ophthalmology, Tongji Hospital (Wuhan, China). Baseline measures were defined as the results of systemic and ophthalmic assessments before gene therapy. A BCVA improvement of 0.3 logarithm of the minimum angle of resolution (logMAR; 3 lines) or more was considered clinically significant. A 10% increase in VF index (VFI) or a 3-dB decrease in mean deviation (MD) was considered a significant increase in the VF function. The recommendations of Beck et al3Beck R.W. Maguire M.G. Bressler N.M. et al.Visual acuity as an outcome measure in clinical trials of retinal diseases.Ophthalmology. 2007; 114: 1804-1809Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar for BCVA analysis in a small sample size were followed. The Wilcoxon rank-sum test was adopted to compare the BCVA score between baseline visit and last follow-up visit. The quasi–least-square method with Markov covariance structure was performed using GEEQBOX software (Institut für Statistik, Universität Innsbruck, Innsbruck, Austria) to explore the BCVA dependence on time or treatment. Among the 8 patients (of 9 treated patients) who completed the 75- to- 90-month follow-up visits, 6 patients maintained clinically significant improvement in BCVA (Table S1, available at www.aaojournal.org) and none reported adverse events. Slit-lamp examination showed no anterior or posterior segment abnormalities, and routine systemic tests showed normal results in all patients. The BCVA trends in 9 treated patients are shown in Figure 1. In patient 1, the visual acuity in both eyes began to improve after the first injection (left eye). In patient 2, the BCVA of both the injected and noninjected eyes improved significantly by 0.6 and 0.5 logMAR, respectively, compared with baseline and the 90-month follow-up visit. However, visual acuity was slightly lower at 75 to 90 months compared with that at the 36-month follow-up. In patient 3, BCVA in the injected eye was stable at 36 months compared with that at baseline but decreased by 0.6 logMAR at 75 to 90 months, and the noninjected eye maintained the 0.3-logMAR gain after treatment. In patient 4, BCVA improved by 0.8 and 0.3 logMAR in the injected and noninjected eyes, respectively, compared with that at baseline and the 80-month follow-up visit. In patient 5, the BCVA remained unchanged from baseline at all time points up to 77 months of follow-up. However, the patient stated that he could see his palmprint clearly 3 months after treatment. In patient 6, the BCVA of both injected and noninjected eyes improved by 1.0 logMAR compared with that at baseline and 75 months of follow-up, representing the best visual acuity recovery among all treated patients. In patient 7, the BCVA of both injected and noninjected eyes improved by 0.3 logMAR compared with that at baseline and 75 months of follow-up, representing a stable visual acuity improvement in the injected eye and a slight improvement in the noninjected eye as compared with that at the 36-month follow-up. In patient 9, after a transient improvement in BCVA up to 6 to 12 months, both eyes did not show improvements in BCVA beyond baseline for the remainder of the study period. In patient 1, both VFI and MD improved after treatment in the left eye and decreased 1 year after treatment in the right eye. In patient 2, at 90 months, both VFI and MD improved significantly and synchronously with BCVA compared with those at baseline and the 36-month follow-up after gene therapy, at a rate of approximately 10% per year. In patient 3, at 36 months, VFI, MD, and BCVA improved before injection, but decreased at 80 months after injection in the injected eye. The VF of patients 4 and 5 did not change significantly compared with that at baseline. In patient 6, the VFI and MD deteriorated at the 12-month follow-up, but improved significantly at the 24-, 36-, and 80-month follow-ups. Patients 7 and 9 showed no apparent VF recovery. We found the gene therapy treatment to be well tolerated and safe. In this long-term follow-up study in 8 patients treated with gene therapy, we observed no systemic or ocular adverse events. The viral vectors used in gene therapy inevitably induce the immune system, causing local and systemic reactions that affect adeno-associated virus 2 entry into the target cells, potentially affecting protein expression and therapeutic benefit. The long-term results found in the study suggest that the short-term use of oral glucocorticoids (1 week before gene therapy administration and approximately 4 weeks after gene therapy) to suppress such immunity did not confound the treatment results. The long-term durability results further demonstrate the potential of gene therapy treatment for LHON patients. Oral idebenone (ClinicalTrial.gov identifiers, NCT00747487, NCT02771379, and NCT02774005) provides slight visual benefits and the potential to change color vision and maintains existing vision in patients with early onset (<1 year) LHON. We observed that visual recovery was most significant in patients who received gene therapy treatment at a younger age and within 1 to 2 years of disease onset. It is possible that younger age and early disease onset are associated with a thicker retinal nerve fiber layer and a higher number of surviving retinal ganglion cells. A larger clinical study is required to confirm this hypothesis. An interesting phenomenon observed in this study is the synchronous visual improvement in the treated and nontreated eye after gene therapy administration; similar findings have been reported in 39 LHON patients who received the GS010 (recombinant adeno-associated viral vector serotype 2 containing the wild-type ND4 gene)4GenSight BiologicsGenSight Biologics reports positive follow-up results at week 72 of the RESCUE phase III clinical trial of GS010 in Leber hereditary optic neuropathy (LHON).https://www.businesswire.com/news/home/20190416006022/en/?from=singlemessage&isappinstalled=0Google Scholar gene therapy product and by Feuer et al.5Feuer W.J. Schiffman J.C. Davis J.L. et al.Gene therapy for Leber hereditary optic neuropathy: initial results.Ophthalmology. 2016; 123: 558-570Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar The RESCUE and REVERSE clinical studies of a single intravitreal injection of GS010 in patients with LHON demonstrated good safety profile and provided direct evidence that a therapeutic gene was transferred from the injected eye to the uninjected contralateral eye of primates, supporting the mechanism for bilateral visual improvement with unilateral GS010 gene therapy.6GenSight BiologicsGenSight Biologics reports evidence of GS010 DNA transfer to contralateral eye of primates unilaterally injected with GS010 gene therapy.https://www.businesswire.com/news/home/20191008006015/en/GenSight-Biologics-Reports-Evidence-GS010-DNA-TransferGoogle Scholar, 7Vignal C. Uretsky S. Fitoussi S. et al.Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy.Ophthalmology. 2018; 125: 945-947Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 8Bouquet C. Vignal Clermont C. Galy A. et al.Immune response and intraocular inflammation in patients with Leber hereditary optic neuropathy treated with intravitreal injection of recombinant adeno-associated virus 2 carrying the ND4 gene: a secondary analysis of a phase 1/2 clinical trial.JAMA Ophthalmol. 2019; 137: 399-406Crossref PubMed Scopus (56) Google Scholar In conclusion, this long-term study demonstrated further the potential of rAAV2-ND4 gene therapy as a promising safe and effective treatment for LHON patients. To confirm further the efficacy and safety of rAAV2-ND4 gene therapy, a large sample study is warranted. We currently are conducting a large-scale study (ClinicalTrials.gov identifier, NCT03153293) of gene therapy for LHON, and some results have been published.9Zhang Y. Li X. Yuan J. et al.Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.Clin Exp Ophthalmol. 2019; 47: 774-778PubMed Google Scholar Download .docx (.01 MB) Help with docx files Table S1