LHON therapy: Excellent safety and potential visual benefits

The intravitreal injection of a recombinant AAV2/2 vector with the wild-type ND4 gene might provide a safe and effective avenue to treat patients with Leber’s hereditary optic neuropathy.

Reviewed by Jose Alain Sahel, MD

Paris-The intravitreal injection of a recombinant AAV2/2 vector with the wild-type ND4 gene may be a big step forward in treating patients with Leber’s hereditary optic neuropathy (LHON). In a study evaluating the technology in LHON patients, preliminary data over 15 patients at 48-week follow up showed visual acuity improvements in patients who received the well-tolerated vector within 2 years of the start of vision loss.

During that same time frame, color vision, and visual field showed some improvement more specifically in patients with better baseline values.

Related: Genetic mutation findings in Spanish retinitis pigmentosa

LHON affects the optic nerve at the level of the retinal ganglion cells. Three types of mitochondrial DNA mutations are seen in 95% of the affected patients, i.e., ND4, ND1, and ND6. The first is the most severe and the most frequent of the three and leads to a defect in the complex 1 respiratory chain and degeneration of the retinal ganglion cells and optic nerve.

The result is acute loss of the central vision that occurs bilaterally usually within 8 weeks for 50% of the patients. There currently is no treatment available that can significantly improve the vision, explained Jose Alain Sahel, MD, Professor of Ophthalmology at Pierre and Marie Curie University Medical School, Paris.

Dr. Sahel and his colleagues started their search for a treatment 12 years ago when they began exploring AAV2-based gene therapy to restore the ND4 function. They created an animal model of LHON in which to transfer the ND4 gene.

More: Gene therapy improves functional vision in Leber congenital amaurosis

This approach, GS010 (AAV2/2-ND4), involved using a mitochondrial targeting sequence, a unique and proprietary technology which allows expression of mitochondrial proteins into the mitochondria to correct the genetic defect. By so doing, they showed that the protein was expressed and the phenotype corrected in mutant rats.

Subsequent research projects showed a strong proof of concept in animals, in vitro validation in fibroblast cells from patients with LHON, the absence of toxicity in primates, and the evaluation of the safety and tolerability of the vector in a phase Ib/IIa, the first trial in humans.



Dr. Sahel, who is also director of the Institut de la Vision, and chairman of the department of ophthalmology, Centre Hospitalier National d’Ophtalmologie des XV-XX Paris, presented the preliminary results of the Phase Ib/IIa.

In the dose-escalation trial performed in one center, patients with chronic LHON were given one intravitreal injection in the eye with the worse visual acuity. Then they were followed for 48 weeks followed by an extension study lasting more than 4 years to evaluate the safety. The VA in all patients was worse than 20/200 in both eyes. The primary objective of the study was to determine the safety and tolerability of the vector and the bio-dissemination and immune responses. The secondary objective was to determine the effect on the VA and other visual function.

Four doses were tested in five cohorts that included three patients in each cohort: 9E9, 3E10, 9E10 and 1,8E11 vg/eye, and the third dose was used during the extension cohort. Data safety monitoring was performed before each dose escalation.

The mean patient age was 49.5 years; 86.6% were men. The mean age at disease onset was 42.3 years (range, 32-53 years); the average disease duration at treatment was 5.9 years (range, 0.62-22.2 years).

At the time of this report, nine patients completed the follow-up evaluation at 48 weeks, according to Dr. Sahel.

VA improvement


“No deaths or adverse events leading to study discontinuation occurred. No systemic or serious adverse events occurred that were related to GS010 or the study procedures,” Dr. Sahel reported. One serious adverse event that was not related to the injection, i.e., thoracic pain 7 to 8 months following the injection, occurred.

Fifty-seven ocular treatment-related adverse events occurred, the most common of which was ocular inflammation in 24 eyes; 13 adverse events were related to the study procedure, the most common of which were increased intraocular pressure (IOP) and keratitis. All treatment-related events were considered mild with the exception of four: two moderate IOP increases, one case of severe anterior chamber inflammation, and one case of severe vitreous inflammation.

All IOP increases either resolved spontaneously or with topical therapy. Dr. Sahel pointed out that the injection volume has decreased to 90 microliters from 180 microliters in the phase III trials. The cases of inflammation all responded to topical anti-inflammatory therapy, except for one patient treated with an oral medication.

“The preliminary results of the secondary endpoints showed that there was a beneficial non statistically significant trend (p=0,06) in VA improvement in patients treated sooner than 2 years after the disease onset compared with patients treated more than 2 years after the disease onset,” Dr. Sahel reported.

Color vision


Regarding color vision, the same type of effect was seen when the patients were treated earlier rather than later in the disease process. “There was a significant effect in favor of the treated eye in the patients treated before 2 years after disease onset,” he said.

In patients with a very narrow visual field, no benefit was seen after the injection. However, in those with a larger baseline visual field, there was a significant [P=0.014] effect of the injection in favor of the treated eye when compare to baseline.

He concluded, “The duration of vision loss appears to impact the magnitude of the treatment effect for several visual functions.  Trends of positive treatment effects are seen in treated eyes within 2 years of onset of visual loss. The sustainability of the trends will be evaluated week 48 in all patients.   Therefore, two phase III trials (RESCUE NCT02652767, Principal Investigator Professor Nancy Newman, Atlanta,; REVERSE NCT02652780, Principal Investigator Professor Patrick Yu Wai Man, UK) in patients with early-onset disease are ongoing in Europe in Paris, London, Munich, and Parma and the US in Atlanta, Philadelphia, and Los Angeles to confirm the product efficacy.”

Enrollment in the Phase III began in February 2016.


Jose Alain Sahel, MD

E: j.sahel@gmail.com

This article was adapted from Dr. Sahel’s presentation at the 2015 meeting of the American Academy of Ophthalmology. Dr. Sahel is co-founder, consultant, and co-patenter of Gensight.

The technology allowing the targeting of the protein to the mitochondrion has been developed by Marisol Corral-Debrinski, PhD, in collaboration with Dr. Sahel at Institut de la Vision, patented by the French INSERM and is exclusively licensed to GenSight Biologics, Paris. Dr. Sahel holds a patent on the AAV2/2 vector and is co-founder of GenSight Biologics. The trial (NCT02652780, Principal Investigator Dr. Catherine Vignal-Clermont )was sponsored by GenSight Biologics and conducted in collaboration with Professor Sahel and Dr. Catherine Vignal of the Quinze-Vingts National Ophthalmology Hospital/Institut de la Vision and Fondation Ophtalmologique Rotschild.