Target Amyloid Aggregation as a New Therapeutic Approach to Treat the Central Nervous System in Sanfilippo Syndrome
Update: April 2021
Cure Sanfilippo Foundation has co-funded a translational research grant to build upon this research. Learn more.
Update: April 2020
Findings from this research project were published in:
Molecular Therapy | “The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease.”
Frontiers In Molecular Neuroscience | “Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases.”
From Frontiers In Molecular Neuroscience …
“Further studies in MPS-IIIA mice have showed that α-synuclein progressively accumulates together with other amyloid proteins, including PrP, tau, and Aβ mostly into the lysosomes of neuronal cell bodies, thus exerting a gain of neurotoxic function by affecting ALP (Monaco et al., 2020). Indeed, inhibiting amyloid aggregation in MPS-IIIA mice by using CLR01, a “molecular tweezer” that acts as a broad-spectrum inhibitor of protein self-assembly (Attar and Bitan, 2014) reduced lysosomal enlargement and re-activates autophagy, thus ameliorating neurodegenerative signs (Monaco et al., 2020). “
Cure Sanfilippo Foundation has awarded funds to the Telethon Institute of Genetics and Medicine (TIGEM) in Italy to study the effect of a new drug compound on the buildup of toxic proteins in the brains of those affected by Sanfilippo Syndrome.
Project lead Alessandro Fraldi specializes in the study of neurodegeneration in lysosomal storage diseases (LSDs) and novel treatment approaches. Under his lead, the Fraldi team aims to build upon their preliminary data supporting the effects of a novel drug compound in reducing the effects of harmful accumulated proteins in the brain of Sanfilippo animals. The drug functions by a different mechanism of action than previously tried in other neurodegenerative diseases characterized by protein aggregation.
“We are pleased to support this new approach to addressing a key feature of neurodegeneration. The many biochemical similarities among neurodegenerative conditions like Alzheimer’s Disease, Parkinson’s Disease and Sanfilippo Syndrome are striking. Research aimed at these common features offers the opportunity to find ways to improve the lives of loved ones with these devastating conditions”, said Dr. Cara O’Neill, Scientific Director of Cure Sanfilippo Foundation.
Initial proof of concept work has been conducted using the MPSIIIA mouse model. Inclusions of aggregated proteins was shown to be a general feature of MPSIIIA brain disease in which such aggregation progressively builds up as neurodegeneration is seen. Preliminary data indicates that the drug is able to clear protein aggregation, thus reducing inflammation and oxidative stress.
In this project, a large efficacy study will be performed testing the drug’s effects on toxic protein clearance, inflammation, nerve signaling, and behavior in MPSIIIA mice. Dr. Fraldi has also assembled a team of collaborators to further evaluate these findings in the other subtypes of Sanfilippo syndrome (MPSIIIB-D).
Start Date: April 2018