Author: Qiutang Li
Co-authors: Yong Zhang, Xin Li, Kunwei Ruan, Congwu He, Di Zhang, Bin Li
AbstractPurpose: The study was to evaluate the clinical safety and efficacy of single intravitreal injection (IVT) of recombinant adeno-associated virus serotype 2-based gene therapy (rAAV2-ND1, NFS-02) at different concentrations in the treatment of Leber's hereditary optic neuropathy with ND1 mutation. Recently, NFS-02 has been granted orphan drug designation for the treatment of LHON associated with ND1 mutation by the US FDA.
Setting: LHON is an inherited mitochondrial disorder characterized by bilateral vision loss due to the degeneration of retinal ganglion cells. Approximately 13%-25% of LHON cases are caused by G3460A point mutation in ND1 mitochondrial gene. There is currently no effective treatment for LHON.
Methods: 10 LHON subjects aged between 5 and 65 years old carrying the ND-1-G3460A mutation were enrolled. Open-label gene therapy trial (CTR2000041574) of a single unilateral IVT injection of NFS-02 at 1.5 x108 vector genome (vg) (group 1, n=6) and 1.5 x109 vg (group 2, n=4) in 0.05 mL/eye was conducted. The incidence of adverse events or serious adverse events including liver and kidney function in plasma, best-corrected visual acuity (BCVA) quantified by using the LogMAR chart test, optical coherence tomography (OCT), computerized visual field, and retinal nerve fiber layer (RNFL) were compared before and after treatment at 1-, 3-, 6-, and 12-month intervals.
Results: A total of 10 ND1-LHON subjects were enrolled. The mean age of these subjects was 24.17 ± 5.61 years [Min: 13; Max: 33]. None of the subjects in this study reported drug-related serious adverse events. 12 months after injection, a clinically meaningful improvement from the baseline at least -0.3 LogMAR (+15 ETDRS letters) was reported in 66.7% treated eyes (n=6) at 1.5 x108 vg/0.05 mL/eye and 50% treated eyes (n=4) at 1.5 x109 vg/0.05 mL/ eye. Bilateral improvement of BCVA was observed after the unilateral IVT injection of NFS-02 at 1.5 x109 vg/0.05 mL/ eye (-0.15 LogMAR and -0.22 LogMAR mean BCVA for treated eyes and untreated eyes respectively, n=4, p=75.4%), but not at 1.5 x108 vg/0.05 mL/eye (-0.21 LogMAR and -0.05 LogMAR Mean BCVA for treated eyes and untreated eyes respectively, n=6, p=3.7%).
Conclusions: Intravitreal gene therapy with NFS-02 resulted in clinically meaningful and sustained BCVA improvement without toxicity. The statistically significant improvement of BCVA from baseline was maintained at 12 months. This first AAV-ND1 clinical study validates the potential of gene replacement therapy as a promising treatment for LHON. Further study is needed to understand the dose related bilateral nature.
Financial Disclosure: Neurophth Therapeutics