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

Anders Kvanta (), Nalini Rangaswamy, Karen Holopigian, Christine Watters, Nicki Jennings, Melissa S. H. Liew, Chad Bigelow, Cynthia Grosskreutz, Marie Burstedt, Abinaya Venkataraman, Sofie Westman, Asbjörg Geirsdottir, Kalliopi Stasi and Helder André
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Anders Kvanta: Karolinska Institutet
Nalini Rangaswamy: Novartis Institutes for Biomedical Research
Karen Holopigian: Novartis Institutes for Biomedical Research
Christine Watters: Novartis Pharmaceuticals Corporation
Nicki Jennings: Novartis Institutes for Biomedical Research
Melissa S. H. Liew: Novartis Institutes for Biomedical Research
Chad Bigelow: Novartis Institutes for Biomedical Research
Cynthia Grosskreutz: Novartis Institutes for Biomedical Research
Marie Burstedt: University of Umeå
Abinaya Venkataraman: Karolinska Institutet
Sofie Westman: Karolinska Institutet
Asbjörg Geirsdottir: Karolinska Institutet
Kalliopi Stasi: Novartis Institutes for Biomedical Research
Helder André: Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51575-4

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