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

Marinesco-Sjogren syndrome is a rare, early-onset condition impacting multiple body systems, primarily characterized by cerebellar ataxia and myopathy. This syndrome results from loss-of-function mutations in the SIL1 gene, with no existing disease-modifying treatments available.

To explore potential therapies, researchers examined the application of adeno-associated virus (AAV)-mediated gene therapy in a mouse model mimicking the syndrome. Neonatal mice received intracerebroventricular injections of AAV-PHP.eB vectors. These vectors either contained SIL1 encoding genes under a ubiquitous promoter or were specific to Purkinje cells.

Vehicle-treated mice exhibited motor impairment due to Purkinje cell degeneration and endoplasmic reticulum stress pathway activation. However, mice treated with AAV-SIL1 experienced prevention of ataxia onset, preservation of Purkinje cells, and attenuation of stress pathway activation. Crucially, selective restoration of SIL1 expression in Purkinje cells alone was sufficient to restore motor performance, indicating the cell-autonomous contribution of Purkinje cell dysfunction to disease pathogenesis.

The therapeutic efficacy of AAV-SIL1 intervention endured throughout the 26-week observation period, accompanied by improved muscle function and decreased muscle pathology. These findings establish proof-of-principle that AAV-mediated SIL1 gene therapy can effectively prevent both neurological and muscular manifestations of disease, paving the way for translatable gene therapy approaches for Marinesco-Sjogren syndrome.