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

Front Genet. 2023 Mar 24:14:1118649. doi: 10.3389/fgene.2023.1118649. eCollection 2023.

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).

Keywords: adeno-associated virus; gene therapy; neurodegenerative disease; neuronal ceroid lipofuscinosis; rare disease.

Associated data

  • ClinicalTrials.gov/NCT03770572

Grants and funding

This work was supported by funding to JW, KM, and BK from the Fight Batten Disease Foundation and by funding to JW from Amicus Therapeutics. This work also received support from the Sanford Research Histology and Imaging Core within the Sanford Research Center for Pediatric Research and Cancer Biology (NIH P20GM103620 and P20GM103548).