Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial.
Bouquet Céline, Vignal Clermont Catherine, Galy Anne, Fitoussi Serge, Blouin Laure, Munk Marion R, Valero Sonia, Meunier Sandrine, Katz Barrett, Sahel José Alain
AI Summary
This study found that intravitreal gene therapy for LHON caused mild, treatable intraocular inflammation, largely unrelated to viral dose or systemic immune response.
Abstract
Importance
Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated.
Objective
To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4).
Design, setting, and participants: This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye.
Interventions
Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing.
Main outcomes and measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers).
Results
The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers.
Conclusions and relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.
MeSH Terms
Shields Classification
Key Concepts4
Intravitreal administration of recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4) in patients with Leber hereditary optic neuropathy (LHON) was safe and well tolerated.
Thirteen out of 15 patients (86.7%) experienced intraocular inflammation after rAAV2/2-ND4 administration as a single unilateral intravitreal injection in an open-label, dose-escalation phase 1/2 randomized clinical trial.
Mild anterior chamber inflammation and vitritis were reported at all doses of rAAV2/2-ND4 (9 10^9, 3 10^10, 9 10^10, and 1.8 10^11 viral genomes per eye) and all cases were responsive to treatment in patients with Leber hereditary optic neuropathy (LHON) receiving intravitreal gene therapy.
The overall ocular inflammation score (OIS) was not associated with the viral dose administered (9 10^9, 3 10^10, 9 10^10, and 1.8 10^11 viral genomes per eye) of rAAV2/2-ND4 in patients with Leber hereditary optic neuropathy (LHON).
Related Articles5
Leber hereditary optic neuropathy gene therapy.
ReviewVisual function in chronic Leber's hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset.
Clinical TrialFive-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.
Clinical TrialTranscriptomic neuron types vary topographically in function and morphology.
Basic ScienceThe rAAV2-ND1 gene therapy for Leber hereditary optic neuropathy.
Clinical TrialIs this article assigned to the wrong chapter(s)? Let us know.