Gene Therapy for Leber Hereditary Optic Neuropathy

Abstract

Purpose Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. Design In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 109 vg), and the fourth participant was treated at the medium dose (2.46 × 1010 vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Participants Five legally blind patients with G11778A LHON. Main Outcome Measures Loss of visual acuity. Results Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. Conclusions No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

“…Furthermore, the retinal ganglion cell (RGC) promoter we describe here will benefit both basic research 32 and clinical gene therapies targeting RGCs. 33 …”

Development of Optimized AAV Serotype Vectors for High-Efficiency Transduction at Further Reduced Doses

“…[14][15][16]30 At least one of these vectors has also shown to be less immunogenic 31 and, in a recent phase I clinical trial, shown efficacy for the potential gene therapy of Leber's hereditary optic neuropathy. 32 We have also described strategies involving genome modifications that lead to the generation of ssAAV vectors with which high efficiency of transgene expression can be achieved. 17 In the present studies, we combined the two strategies to generate the optimized AAV vectors.…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Initial results from study NCT02161380 that treated five LHON patients carrying the G11778A mutation with ScAAV2-P1ND4v2 have been reported (Feuer et al 2016). At the 3-month time point, none of the patients lost vision and only minor adverse events were reported; these consisted of a transient increase of intraocular pressure (IOP), keratitis, subconjunctival hemorrhage, and a sore throat; a transient increase in neutralizing antibodies against AAV2 in 1 participant was also reported.…”

“…Gene therapy has been proposed for treatment of LHON and active trials are currently enrolling subjects (Feuer et al 2015;Peragallo and Newman 2015;YuWai-Man et al 2014). Allotopic rescue is currently the modality being studied in the USA.…”

“…This technique has been successful in an animal model of LHON and is now in human clinical trials. Safety of the vector in human patients was reported in 2015 (Feuer et al 2015). Whether this or a different gene therapy approach will be successful awaits the completion of the investigations.…”