Selective HDAC6 inhibitors as a novel treatment for CNS pathology in MPS-I
Awardee: Nicolina Cristina Sorrentino
Institution: University of Naples " Federico II"
Grant Amount: $60,378.00
Funding Period: February 1, 2025 - January 31, 2026
Summary:
The Mucopolysaccharidoses (MPS) are a group of inherited disorders caused by mutations in genes affecting systemic organs with severe involvement of brain and retina tissues. Since the symptoms occur during the first years of life, an early therapeutic intervention to treat the systemic problems is essential. Recently, scientists discovered that MPS is linked to other serious brain diseases like Alzheimer's and Parkinson's. MPS type I represents the most severe MPS caused by the deficiency of Iduronidase (IDUA) protein, responsible for breaking down substances, like glycosaminoglycans (GAG), leading to systemic and cerebral symptoms. The treatment of brain pathology represents the primary goal in developing any therapeutic approach for MPS-I. Along with glycosaminoglycan accumulation that represent the primary storage, another important player of MPS disorder is represented by the block of the cellular 'garbage disposal' process, called autophagy, which cause the accumulation of secondary toxic materials and strongly influence the neuropathology progression. Current therapeutic strategies are based on the restoration of only the functional IDUA protein, which is not sufficient for removing all the secondary storage present in the cells of MPS-I patients. In this light, a new treatment stimulating autophagy and tackling accumulation of toxic materials might restore CNS and retinal health in MPS-I. For this reason, we propose a new pharmacological approach aimed at reactivating the autophagy mechanism, removing storage toxic material, promoting neuroprotection in brain and retina of MPS-I. Advanced pharmacology and cellular biology techniques will be employed to develop selective compounds in order to target and treat MPS-I brain cells. Additionally, biochemical, molecular and immunofluorescence analyses will be performed on MPS-I cell lines in order to validate the effectiveness of the therapy in restoring neuronal function and reducing the accumulation of toxic materials.