Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA

TLDR

Late infantile neuronal ceroid lipofuscinosis is an autosomal recessive neurodegenerative lysosomal storage disease that is fatal by age 8–12. The study proposes further research to evaluate the safety and efficacy of AAV‑mediated gene therapy for LINCL. Twelve CNS sites in ten children received a total dose of 2.5 × 10¹² AAV2 vector particles carrying human CLN2 cDNA, with neurological rating scales and MRI parameters used to assess decline over 18 months. No unexpected serious adverse events were linked to the vector, but a subject died post‑surgery and mild humoral responses occurred; MRI rates of decline were slower and the primary neurologic rating scale showed a significantly reduced decline, suggesting slowed disease progression despite limited sample size.

Abstract

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 × 1012 particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2CU hCLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2CU hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAVmediated gene therapy for LINCL are warranted.