Lenadogene nolparvovec gene therapy in leber hereditary optic neuropathy

Leber Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited mitochondrial genetic disorder characterized by sudden, painless vision loss, and represents a significant unmet medical need. The pathophysiology of LHON is characterized by the selective loss of Retinal Ganglion Cells (RGCs) and their axons, leading to rapidly progressive bilateral vision loss. LHON was the first human inherited disease to be linked to point mutations in mitochondrial DNA (mtDNA) and remains the most common inherited genetic mitochondrial disorder. The disease is primarily caused by three mitochondrial DNA point mutations — m.3460G>A, m.11778G>A, and m.14484T>C — located in the MT-ND1, MT-ND4, and MT-ND6 genes, respectively. Of these, the m.11778G>A mutation is both the most prevalent, accounting for 75% of cases, and the most severe in terms of clinical phenotype. RGCs appear to be selectively vulnerable to mitochondrial dysfunction which triggers apoptotic cell death, optic nerve degeneration and optic atrophy.

Lenadogene nolparvovec (GS010)/Lumevoq^®) is a gene therapy based on a recombinant adeno-associated viral vector (rAAV2/2) encoding the wild-type human ND4 protein. It is designed to address the underlying cause of LHON in patients harboring the m.11778G>A mutation by restoring ND4 protein expression, thereby improving mitochondrial Complex I function and preserving retinal ganglion cells. The gene therapy is delivered by Intravitreal Injection (IVT), the optimal route for transducing RGCs. The serotype 2 (rAAV2/2) was selected for its high transduction efficiency in the inner retinal layers, primarily the central RGCs that are primarily affected in LHON.

Four multicenter Phase 3 clinical trials — REFLECT, RESCUE, REVERSE and RESTORE — demonstrated sustained, bilateral improvement in Best-Corrected Visual Acuity (BCVA) after unilateral or bilateral intravitreal injection of lenadogene nolparvovec. A total of 189 patients were treated across these trials, with results showing meaningful recovery of visual function. Early access programs conducted in France, the United States and Israel, further support the therapy’s potential to address a major therapeutic gap in mitochondrial optic neuropathies.

Dr. Taiel completed her doctorate in Medicine with board certified in Ophthalmology from Lariboisiere Saint Louis University, Paris, France, in 1993, and her Associate Professor degree in 1998. Dr Taiel completed her internship at academic Paris hospitals, was an Associate Professor of Ophthalmology, served as an Ophthalmology Department Head, and ran Surgical and Medical Ophthalmology private practice.  After 13 years of Ophthalmology public and private practice, Dr Taiel has been engaged in the Pharma Industry for 20 years; she brings extensive experience and expertise in drug clinical development, gene therapy, and medical affairs. She started her carrier at Servier company headquarter, and then worked in Ophthalmology area at Pfizer for several years; she then held international and management positions in various therapeutic areas, including both technical and supervision duties, at Eli Lilly Company for many years. Then, as VP Clinical Development, she led Clinical Development and Operations, to develop antisense oligonucleotides in Inherited Retinal diseases at ProQR Therapeutics. She then moved to GenSight-Biologics in 2018, to supervise the Medical Department and lead Gene Therapy programs in Inherited Retinal and Neuro-Ophthalmology diseases, as the CMO of the company. Dr. Taiel has authored numerous protocols and articles published in peer reviewed journals, and made critical contributions to successful clinical development and launch of many products. She brings extensive years of experience from both academic medicine and pharma industry.