Preclinical efficacy study of PERK signaling inhibitors and TUDCA in Marinesco-Sjögren syndrome

Individuals with Marinesco-Sjögren syndrome (MSS), a rare genetic disease of infancy, suffer various disabilities, including loss of motor coordination due to cerebellar degeneration, and skeletal muscle weakness. After a progressive phase, symptoms stabilize and patients live to old age. Therefore, any pharmacological treatment that delays or attenuates cerebellar degeneration and/or muscle pathology can significantly improve their quality of life. We found that inhibiting the kinase PERK with the experimental drug GSK2606414 delays cerebellar degeneration, and ameliorates motor function and muscle pathology in a MSS mouse model. However GSK2606414 is toxic to the pancreas and does not completely rescue the mouse disease. In this project, we plan to test trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling without pancreatic toxicity. We also plan to test TUDCA, a drug which has a different mechanism of action, alone or in combination with trazodone or DBM. Since these drugs are already used in the clinical practice for other purposes, positive results in the mouse model may lead to their rapid repurposing for MSS.