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 neurological and muscular disease in the woozy mouse model of SIL1 deficiency. Neonatal mice received intracerebroventricular injections of AAV-PHP.eB vectors expressing SIL1 under the control of either a ubiquitous or a Purkinje cell-specific promoter. Vehicle-treated woozy mice developed progressive motor impairment accompanied by extensive Purkinje cell degeneration, thinning of the cerebellar molecular layer, marked astrogliosis and activation of endoplasmic reticulum stress pathways. In contrast, AAV-SIL1 treatment prevented the onset of ataxia and substantially preserved cerebellar architecture, including Purkinje cells and molecular-layer thickness, while reducing astrogliosis and endoplasmic reticulum stress. Selective restoration of SIL1 expression in Purkinje cells was sufficient to rescue motor performance, supporting a major cell-autonomous contribution of Purkinje cell dysfunction to cerebellar disease. Therapeutic benefit was maintained throughout the 26-week observation period, the longest time point examined, with treated mice remaining behaviorally indistinguishable from heterozygous controls. AAV-SIL1 treatment also improved muscle function and markedly attenuated skeletal muscle pathology, with transgenic SIL1 expression in muscle reaching levels comparable to those in heterozygous controls. These findings provide proof-of-principle that AAV-mediated SIL1 gene therapy can prevent the neurological and muscular manifestations of Marinesco-Sjogren syndrome and identify Purkinje cells as a critical cellular target for preventing cerebellar dysfunction.