Pharmacological stimulation of autophagy to rescue proteinopathy and cognitive decline in Mucopolysaccharidosis-IIIA

In Sanfilippo disease, the lack of a gene that encodes for an enzyme responsible for the degradation of the sugar heparan sulfate, leads to an engulfment in the degradation system of waste substances in the cell: the autophagic/lysosomal system. Therefore, this system can no longer physiologically work as “incinerator” of waste substances, leading to the formation of secondary storages, such as those of beta amyloid, which are known to be responsible for age-related neurodegenerative diseases, such as Alzheimer's disease. Under the pressure of these storages, the neurons, progressively die and children with Sanfilippo syndrome develop infantile dementia.

One of the most promising therapeutic strategies, to date, is to find therapies that stimulate, in an almost physiological way, the degradative capacity of the autophagic-lysosomal system; we know, in fact, that its excessive stimulation has serious side effects.

Our group has found a substance capable of cleaning up protein aggregates in other age-related disease models and in in vitro (cellular) models of MPS-IIIA. This substance is part of the natural components of our cells and appears to be altered in MPS-IIIA, in a manner related to the neuropathological manifestations.

In this project we propose to test, in vivo, this substance on memory and aggregates formation in a mouse model of MPS-IIIA and to verify, if and how, this substance can be regulated and regulates the disease progression in children. This will provide proof-of-concept of its efficacy necessary to design a clinical trial in patients.