Preclinical study of Fluoxetine efficacy in MPS-I mouse model
Awardee: NICOLINA CRISTINA SORRENTINO
Institution: FONDAZIONE TELETHON ETS-TIGEM
Grant Amount: $60,000.00
Funding Period: February 1, 2023 - January 31, 2024
Summary:
Mucopolysaccharidosis type I (MPS-I) is a severe inherited disorder characterized by deficient activity of lysosomal enzyme α-L-Iduronidase (IDUA) responsible for the degradation of the glycosaminoglycans, leading to systemic symptoms and a shortened lifespan. Current therapies are mainly palliative with no benefit for the brain pathology. Several works indicated the importance of the lysosomal and autophagy alterations as major players in the development of brain and peripheral tissue pathology in Lysosomal Storage Disorders (LSD). Importantly, in our recent work we combined automated microscopy screening and repurposing of FDA compounds to identify approved drugs able to correct lysosomal dysfunction in LSD. Our drug survey resulted in the identification of Fluoxetine, a central nervous system drug and one of the most prescribed medicines in adults and children. Interestingly, we showed that Fluoxetine boosts lysosomal function and promotes glycosaminoglycans degradation in MPS-IIIA, MPS-I and MSD cell lines. Furthermore, our recent preclinical study demonstrated the effectiveness of Fluoxetine in the amelioration of brain and somatic pathological hallmarks of MPS-IIIA such as the accumulation of storage materials, inflammation, and slow-down cognitive deterioration in MPS-IIIA mouse model. Based on these promising results, we propose to validate the effectiveness of the Fluoxetine administration for the treatment of brain and peripheral pathology in a mouse model of MPS-I.