Neonatal AAV-SIL1 gene therapy prevents Marinesco-Sjögren syndrome in mice

Marinesco-Sjogren syndrome is a rare early-onset multisystem disorder characterized primarily by cerebellar ataxia and myopathy and caused by loss-of-function mutations in SIL1. No disease-modifying therapy is available. We investigated whether adeno-associated virus (AAV)-mediated gene therapy could prevent disease in the woozy mouse model. Neonatal mice received intracerebroventricular injections of AAV-PHP.eB vectors encoding SIL1 under the control of a ubiquitous or a Purkinje cell-specific promoter. Vehicle-treated woozy mice developed motor impairment associated with Purkinje cell degeneration and activation of endoplasmic reticulum stress pathways. In contrast, AAV-SIL1 treatment prevented the onset of ataxia, preserved Purkinje cells, and attenuated stress pathway activation. Selective restoration of SIL1 expression in Purkinje cells was sufficient to rescue motor performance, supporting a cell-autonomous contribution of Purkinje cell dysfunction to disease pathogenesis. Therapeutic efficacy was maintained throughout the 26-week observation period and was accompanied by improved muscle function and attenuation of muscle pathology. These findings provide proof-of-principle that AAV-mediated SIL1 gene therapy can prevent both neurological and muscular manifestations of disease and support the development of translatable gene therapy approaches for Marinesco-Sjogren syndrome.