Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy

Xing Wan, Han Pei, Min-jian Zhao, Shuo Yang, Wei-kun Hu, Heng He, Si-qi Ma, Ge Zhang, Xiao-yan Dong, Chen Chen, Dao-wen Wang, Bin Li, Xing Wan, Han Pei, Min-jian Zhao, Shuo Yang, Wei-kun Hu, Heng He, Si-qi Ma, Ge Zhang, Xiao-yan Dong, Chen Chen, Dao-wen Wang, Bin Li

Abstract

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.

Figures

Figure 1. Retinal appearance and morphologic features…
Figure 1. Retinal appearance and morphologic features before and after intravitreal injection of rAAV2- ND4 in the nine patients.
(A) Representative 30° fundus photographs taken with a NIDEK Auto Fundus Camera show the disk and macula of injected eyes of patients before intravitreal injection. The retinal structure of the nine patients was normal. (B to E) 30° fundus photographs show the disk and macula of injected eyes of the nine patients at months 1, 3, 6, and 9 after intravitreal injection, respectively. No apparent retinal abnormality was found.
Figure 2. Visual acuity (log MAR) before…
Figure 2. Visual acuity (log MAR) before and after intravitreal injection of rAAV2- ND4 in the nine patients.
Mean best-corrected visual acuity (BCVA) values of injected and uninjected eyes before and 1, 3, 6 and 9 months after intravitreal injection are shown.
Figure 3. Visual field of the injected…
Figure 3. Visual field of the injected eye of patient 4 at the 9-month follow-up.
The visual field of the injected eye of patient 4 was gradually improved at 1, 3, 6, and 9 months after treatment, and the visual field at 6 months after treatment was the best.
Figure 4. Visual field index (VFI) of…
Figure 4. Visual field index (VFI) of injected and uninjected eyes of the nine patients.
Mean VFI values of injected and uninjected eyes before and 1, 3, 6 and 9 months after intravitreal injection are shown. Eight patients had their VFI improved after treatment; the VFI of patient 5 was not improved.
Figure 5. Mean defect (MD) of injected…
Figure 5. Mean defect (MD) of injected and uninjected eyes of the nine patients.
Mean MD values of injected and uninjected eyes before and 1, 3, 6, and 9 months after intravitreal injection.

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