Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease

• Published in: Frontiers in genetics 2023-03, Vol.14, p.1118649-1118649
• Main Authors: Johnson, Tyler B, Brudvig, Jon J, Likhite, Shibi, Pratt, Melissa A, White, Katherine A, Cain, Jacob T, Booth, Clarissa D, Timm, Derek J, Davis, Samantha S, Meyerink, Brandon, Pineda, Ricardo, Dennys-Rivers, Cassandra, Kaspar, Brian K, Meyer, Kathrin, Weimer, Jill M
• Format: Article
• Language: English
• Subjects: adeno-associated virus; gene therapy; Genetics; neurodegenerative disease; neuronal ceroid lipofuscinosis; rare disease
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2023.1118649

CLN3 disease, caused by biallelic mutations in the gene, is a rare pediatric neurodegenerative disease that has no cure or disease modifying treatment. The development of effective treatments has been hindered by a lack of etiological knowledge, but gene replacement has emerged as a promising therapeutic platform for such disorders. Here, we utilize a mouse model of CLN3 disease to test the safety and efficacy of a cerebrospinal fluid-delivered AAV9 gene therapy with a study design optimized for translatability. In this model, postnatal day one administration of the gene therapy virus resulted in robust expression of human throughout the CNS over the 24-month duration of the study. A range of histopathological and behavioral parameters were assayed, with the therapy consistently and persistently rescuing a number of hallmarks of disease while being safe and well-tolerated. Together, the results show great promise for translation of the therapy into the clinic, prompting the launch of a first-in-human clinical trial (NCT03770572).