Interim safety and efficacy of gene therapy for RLBP1-associated retinal dystrophy: a phase 1/2 trial

• Published in: Nature communications Vol. 15; no. 1; pp. 7438 - 12
• Main Authors: Kvanta, Anders, Rangaswamy, Nalini, Holopigian, Karen, Watters, Christine, Jennings, Nicki, Liew, Melissa S. H., Bigelow, Chad, Grosskreutz, Cynthia, Burstedt, Marie, Venkataraman, Abinaya, Westman, Sofie, Geirsdottir, Asbjörg, Stasi, Kalliopi, André, Helder
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-09-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 42; 42/41; 631/61/201/2110; 692/308/153; 692/308/2779/109/1940; 692/699/3161/3175; Adaptation; Adolescent; Adult; Atrophy; Carrier Proteins - genetics; Clinical trials; Dark adaptation; Degeneration; Dependovirus - genetics; Dystrophy; Effectiveness; Epithelium; Female; Gene therapy; Genetic disorders; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health services; Humanities and Social Sciences; Humans; Male; Medicin och hälsovetenskap; Middle Aged; multidisciplinary; Mutation; Patients; Retina; Retinal degeneration; Retinal Dystrophies - genetics; Retinal Dystrophies - therapy; Retinal pigment epithelium; Retinaldehyde; Retinaldehyde-binding protein; Safety; Science; Science (multidisciplinary); Sensitivity analysis; Toxicity; Treatment Outcome; Visual field; Visual fields; Visual perception; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51575-4

Gene therapy holds promise for treatment of inherited retinal dystrophies, a group of rare genetic disorders characterized by severe loss of vision. Here, we report up to 3-year pre-specified interim safety and efficacy results of an open-label first-in-human dose-escalation phase 1/2 gene therapy clinical trial in 12 patients with retinal dystrophy caused by biallelic mutations in the retinaldehyde-binding protein 1 (
RLBP1
) gene of the visual cycle. The primary endpoints were systemic and ocular safety and recovery of dark adaptation. Secondary endpoints included microperimetry, visual field sensitivity, dominant eye test and patient-reported outcomes. Subretinal delivery of an adeno-associated viral vector (AAV8-
RLBP1
) was well tolerated with dose-dependent intraocular inflammation which responded to corticosteroid treatment, and focal atrophy of the retinal pigment epithelium as the dose limiting toxicity. Dark adaptation kinetics, the primary efficacy endpoint, improved significantly in all dose-cohorts. Treatment with AAV8-
RLBP1
resulted in the resolution of disease-related retinal deposits, suggestive of successful restoration of the visual cycle. In conclusion, to date, AAV8-
RLBP1
has shown preliminary safety and efficacy in patients with
RLBP1
-associated retinal dystrophy. Trial number: NCT03374657.
This phase I/II clinical trial was designed to assess safety and efficacy of gene therapy for Bothnia dystrophy, an inherited retinal degeneration leading to blindness. Kvanta
et al
. show interim results from 12 patients with meaningfully improved visual function in dim light.