AUTHOR=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. TITLE=Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease JOURNAL=Frontiers in Genetics VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1118649 DOI=10.3389/fgene.2023.1118649 ISSN=1664-8021 ABSTRACT=

CLN3 disease, caused by biallelic mutations in the CLN3 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 CLN3 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).