Understanding and developing therapeutic approaches for Severe Inherited Neurodegenerative Mucopolysaccharidoses type II and type IIIA

MPS are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes and subsequent progressive accumulation of undegraded glycosaminoglycans (GAGs) in different organs. The phenotype of these disorders is complex and characterized by the variable association of visceral, skeletal, muscular and neurological manifestations. Most severe MPS are represented by the Mucopolysaccharidoses type IIIA (MPS-IIIA; Sanfilippo type A; MIM 252900) and Mucopolysaccharidoses type II (MPS-II; Hunter Syndrome). They are caused by inherited defects of the lysosomal hydrolase enzymes lead to the accumulation of GAGs systemically, particularly within the central nervous system (CNS). The treatment of CNS disease is the main goal for the development of any therapeutic approach for these disorders. Currently, there is no effective therapy for the treatment of CNS pathology in MPS-IIIA patients and existing clinical protocols try to alleviate the somatic symptoms rather than treat the causes of the disease. Our studies elucidated on the mechanism of the CNS and retinal pathology and demonstrated the efficacy of the intrathecal gene therapy protocols based on the adeno associated viral vector (AAV)-mediated delivery of lysosome enzymes results in a rescue of brain pathology, including memory deficit, as well as improvement in somatic tissues. The aim of our work is to design novel translational therapeutic strategies based on AAV-gene therapy and drug therapy protocols able to improve the rescue CNS and somatic storage pathology in MPS patients. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.