Preclinical efficacy assessment of AAV-mediated gene therapy and investigation of neurodegenerative mechanisms for drug discovery in Marinesco-Sjögren syndrome

There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic disease of infancy linked to loss-of-function mutations in the endoplasmic reticulum (ER) co-chaperone SIL1. Although SIL1 is expressed ubiquitously, its loss causes the death of only certain body cells, including cerebellar neurons and skeletal muscle fibers. SIL1 mutations lead to accumulation of unfolded proteins and maladaptive ER stress response. However, targeting the ER stress has only partial beneficial effects in the woozy mouse model of MSS. We plan to evaluate the therapeutic efficacy of a neonatal AAV-mediated gene therapy aimed at restoring SIL1 function. We will also employ single cell transcriptomics, proteomics and metabolomics to investigate the mechanisms of selective eurodegeneration. We expect to provide proof-of-principle evidence in support of a potentially resolving gene therapy approach, and to improve our understanding of MSS pathophysiology in order to devise more effective pharmacological treatments.