O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Neurodegenerative proteinopathies involve toxic protein aggregates like tau and alpha-synuclein.
• O-linked N-acetyl-d-glucosamine (O-GlcNAc) modification influences protein aggregation and toxicity.
• Inhibiting O-GlcNAcase (OGA) increases O-GlcNAc levels, offering a therapeutic strategy.

Purpose of the Study:

• To discover and develop a novel small molecule OGA inhibitor, ASN90.
• To evaluate ASN90's efficacy in preclinical models of tauopathies and alpha-synucleinopathies.
• To assess ASN90's potential as a disease-modifying agent for neurodegenerative proteinopathies.

Main Methods:

• Developed and characterized a novel small molecule OGA inhibitor, ASN90.
• Administered ASN90 orally to transgenic mouse models of tauopathy and Parkinson's disease.
• Assessed O-GlcNAcylation of tau and alpha-synuclein, pathological markers, behavioral deficits, and survival rates.

Main Results:

• ASN90 demonstrated brain penetration and engaged the OGA target, increasing O-GlcNAcylation of tau and alpha-synuclein in mice.
• ASN90 prevented tau pathology (NFT formation), motor and breathing deficits, and improved survival in tauopathy models.
• ASN90 slowed motor impairment and reduced astrogliosis in a preclinical Parkinson's disease model.

Conclusions:

• ASN90 is a promising preclinical OGA inhibitor with potential for treating tauopathies and alpha-synucleinopathies.
• OGA inhibitors represent a novel therapeutic approach for neurodegenerative diseases with co-existing tau and alpha-synuclein pathologies.
• ASN90 warrants further clinical development as a multimodal drug candidate for neurodegenerative proteinopathies.