CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine Type 1 Progressive Myoclonus Epilepsy

Abstract

Abstract Unverricht-Lundborg disease (ULD) is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and severely disabling myoclonus, seizures, ataxia, psychiatric disease, dementia and shortened lifespan. This disease is caused by recurrent expansions of an expansion-prone human genome specific dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, expression of the gene. The relatively late onset of symptoms and consistent presence of at least a minimal amount of protein product makes this disease a favourable target for gene replacement therapy. Treated early, these children’s normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene product concerns. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice using intrathecal administration of human CSTB-encoding AAV9 at postnatal days 21 and 60, with mice sacrificed at 2 or 9 months of age, respectively. We observed significant improvement of neuroinflammation and neurodegeneration, as well as amelioration of motor coordination. The data suggest that gene replacement is a promising therapeutic modality for ULD and could spare affected children and families the ravages of this otherwise catastrophic epilepsy.