Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy

Yang, Shuo; Ma, Siqi; Wan, Xing; He, Heng; Pei, Han; Zhao, Min-jian; Chen, Chen; Wang, Daowen; Dong, Xiaoyan; Yuan, Jiajia; Li, Bin

doi:10.1016/j.ebiom.2016.07.002

Cited by 108 publications

(118 citation statements)

References 19 publications

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“…The gene therapy clinical trial in China reported improvements of 3 lines or more in 5 of 9 G11778A LHON patients (7 of their patients were treated more than one year after visual loss) with 36 months of follow-up. 16;17 In our natural history study, 4 only 3 patients recovered vision of 3 lines or more 12 months after the onset of visual loss (7%). In our gene therapy study we observed increases in acuity of approximately 3 lines or more on the ETDRS chart in 3 of 6 patients treated within a year of visual loss.…”

Section: Discussionmentioning

confidence: 66%

Gene Therapy for Leber Hereditary Optic Neuropathy

et al. 2017

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OBJECTIVE To determine the effects of escalating doses of AAV2(Y444,500,703F)-P1ND4v2 in patients with LHON caused by the G11778A mutation in mitochondrial DNA. DESIGN Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,703F)-P1ND4v2 per subject in a phase I clinical trial study initiated in 2014. PARTICIPANTS Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. INTERVENTION Intravitreal injection with the gene therapy vector AAV2(Y444,500,703F)-P1ND4v2 into one eye. Six participants with chronic bilateral visual loss greater than 12 months (Group I), 6 participants with bilateral visual loss less than 12 months (Group II) and 2 participants with unilateral visual loss (Group III) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included ETDRS visual acuity, visual fields, OCT, PERG and neuro-ophthalmic examinations. GEE methods were used for longitudinal analyses. PRIMARY OUTCOME MEASURE Loss of visual acuity. RESULTS For Groups I and II, month 12 average acuity improvements with treatment relative to baseline were 0.24 logMAR. Fellow eyes had a 0.09 logMAR improvement. A post-hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in Group II patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (p=0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute Group II gene therapy patients of 0.96 was greater than that observed in our prior acute natural history patients (0.17 logMAR) p<0.001. Two patients developed asymptomatic uveitis that resolved without treatment. OCT of treated eyes had an average temporal RNFL thickness of 54 μm prior to injection and 55 μm at month 12. For fellow eyes prior to injection it was 56 μm dropping to 50 μm at month 12, p = 0.013. GEE suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by about 0.05 uV (p exchangeable = 0.009). No difference between eyes in outcomes of other visual function measures was evident. CONCLUSIONS Allotopic gene therapy for LHON at low and medium doses appears safe and does not damage the temporal RNFL opening the door for testing of the high dose next.

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Section: Discussionmentioning

confidence: 66%

Gene Therapy for Leber Hereditary Optic Neuropathy

et al. 2017

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“…Our research, however, has ruled out the possibility of spontaneous vision recovery. First, 1 year before clinical treatment, patients with spontaneous VA were excluded, and the improvement of VA in 9 patients treated from 3 months after treatment started to increase with a similar trend [7, 9]. Second, Lam et al [20] also conducted an in-depth study of the effect of increased spontaneous vision on gene therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Using pretherapy VA as the baseline, BCVA was examined using a standard logMAR acuity chart at a distance of 2.5 m (Star Kang Medical Technology Co., Ltd. Wen Zhou, China) [8, 9]. The same ophthalmologists examined the BCVA of both injected and uninjected eyes in 7 patients before gene therapy, and at 3, 6, 9, 24, and 36 months after treatment.…”

Section: Methodsmentioning

confidence: 99%

“…We used gene therapy for the treatment of 9 patients with LHON from 2011 to 2012 (Trial registry: Safety and efficacy study of a single intravitreal injection of rAAV2-ND4 treatment of Leber’s hereditary optic neuropathy; No. NCT01267422; December 2010), with clinical follow-up observation of changes in VA and VF values at different time points [8, 9]. We found that patients with LHON who received a monocular intravitreal injection of AAV2-ND4 and exhibited enhanced VA actually demonstrated VA improvement in both injected and uninjected eyes, or exhibited significant VA improvement in one eye and some improvement in the other eye.…”

Section: Introductionmentioning

confidence: 99%

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Visual Field Variability after Gene Therapy for Leber’s Hereditary Optic Neuropathy

et al. 2018

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Purpose: To assess changes in visual field (VF) values after gene therapy for Leber’s hereditary optic neuropathy (LHON). Methods: VF recovery, VF indices, and mean deviation in injected and uninjected eyes, before and after gene therapy, were examined in 2 groups of patients according to disease duration (≤2 years and > 2 years). Nine patients with LHON were treated by monocular intravitreal injection of AAV2-ND4. Finally, 7 patients were considered for subsequent comparisons; the first and second eyes were treated separately. Results: There were no significant differences in VF indices and mean deviation between injected and uninjected eyes (p = 0.910 and p = 0.929, respectively). However, there was a significant difference before and after injection (p = 0.016 and p = 0.015, respectively). There was no significant difference in VF improvement between patients with ≤2 years’ disease duration and those with a longer disease duration. Conclusion: There was a statistically significant VF improvement after gene therapy. This suggests that monocular intravitreal injection of AAV2-ND4 can improve binocular VF values. This study also suggests that gene therapy can be effective in patients with a disease duration of > 2 years.

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“…With respect to cutting-edge technologies, Sichuan University's West China Hospital in Chengdu recently announced that they are preparing to conduct the world's first human trial using CRISPR gene editing technology (16). In addition, a team of scientists from Tongji Medical College have, in collaboration with FivePlus Molecular Medicine Institute in Beijing, successfully conducted a long-term trial of gene therapy in human patients with a rare genetic disorder known as Leber's hereditary optic neuropathy (LHON) (17,18), more than 10 years after the world's first gene therapy was approved in China (19).…”

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confidence: 99%