The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, are a group of inherited lethal neurodegenerative lysosomal storage disorders. CLN5 disease is caused by mutations in the CLN5 gene encoding a soluble lysosomal lumen protein with cysteine-based S-depalmitoylase activity. Children with CLN5 disease suffer progressive motor dysfunctions, vision loss, seizures and dementia, eventually leading to premature death. It is currently incurable and there is a desperate need for a novel effective therapy. Here we carried out a preclinical study of an adeno-associated virus (AAV) - mediated gene therapy in a transgenic mouse model of CLN5 disease.

 

A single dose of AAV9 vectors carrying the human CLN5 gene driven by either the CAG or the synapsin promoter was administered via intracerebroventricular (ICV) injecton into neonatal Cln5 mice. Treatment efficacy was evaluated by assessment of neurodegeneration and monitoring of locomotor functions and lifespan. In a second trial, single-dose AAV9.hCLN5 was delivered ICV into juvenile early-symptomatic Cln5 mice at 4 weeks of age, to assess treatment efficacy of later stage gene therapy intervention in CLN5 disease.

 

Neonatal ICV administration of AAV9 expressing human CLN5 driven by the neuronal specific synapsin promoter significantly prevented neurodegeneration, improved long-term locomotor functions and extended lifespan of the Cln5 mice. The same vector showed enhanced efficacy when delivered at a juvenile early-symptomatic stage, also resulting in long-term disease attenuation, which provides a particularly practical case for clinical translation. These results indicate that brain-directed AAV gene therapy can be a promising treatment strategy for CLN5 disease.