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

Marinesco-Sjögren 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 currently available. The study tested whether AAV-mediated gene therapy could prevent disease in the woozy mouse model.

Neonatal woozy mice received intracerebroventricular injections of AAV-PHP.eB vectors encoding SIL1 under the control of either a ubiquitous promoter or a Purkinje cell-specific promoter. Vehicle-treated woozy mice developed motor impairment accompanied by 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 alone 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-Sjögren syndrome.