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Start Over Author "Sambri I" Journal molecular therapy the journal of the american society of gene therapy
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2. The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease.

Author

Monaco A, Maffia V, Sorrentino NC, Sambri I, Ezhova Y, Giuliano T, Cacace V, Nusco E, De Risi M, De Leonibus E, Schrader T, Klärner FG, Bitan G, and Fraldi A

Subjects
Amyloid antagonists & inhibitors, Amyloid metabolism, Animals, Brain metabolism, Bridged-Ring Compounds pharmacology, Cell Body metabolism, Disease Models, Animal, Male, Mice, Mucopolysaccharidosis III complications, Mucopolysaccharidosis III metabolism, Neurodegenerative Diseases etiology, Organophosphates pharmacology, Treatment Outcome, Autophagy drug effects, Bridged-Ring Compounds administration & dosage, Mucopolysaccharidosis III drug therapy, Neurodegenerative Diseases drug therapy, Organophosphates administration & dosage
Abstract

Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of the autophagy-lysosomal pathway (ALP) often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, prion protein (PrP), Tau, and amyloid β progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a "molecular tweezer" that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of the ALP was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting the ALP and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2020
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