Neurodegenerative
proteinopathies are characterized by the intracellular
formation of insoluble and toxic protein aggregates in the brain that
are closely linked to disease progression. In Alzheimer’s disease
and in rare tauopathies, aggregation of the microtubule-associated
tau protein leads to the formation of neurofibrillary tangles (NFT).
In Parkinson’s disease (PD) and other α-synucleinopathies,
intracellular Lewy bodies containing aggregates of α-synuclein
constitute the pathological hallmark. Inhibition of the glycoside
hydrolase O-GlcNAcase (OGA) prevents the removal of O-linked
N
-acetyl-
d
-glucosamine (O-GlcNAc) moieties from
intracellular proteins and has emerged as an attractive therapeutic
approach to prevent the formation of tau pathology. Like tau, α-synuclein
is known to be modified with O-GlcNAc moieties and
in vitro
these have been shown to prevent its aggregation and toxicity. Here,
we report the preclinical discovery and development of a novel small
molecule OGA inhibitor, ASN90. Consistent with the substantial exposure
of the drug and demonstrating target engagement in the brain, the
clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation of tau and
α-synuclein in brains of transgenic mice after daily oral dosing.
Across human tauopathy mouse models, oral administration of ASN90
prevented the development of tau pathology (NFT formation), functional
deficits in motor behavior and breathing, and increased survival.
In addition, ASN90 slowed the progression of motor impairment and
reduced astrogliosis in a frequently utilized α-synuclein-dependent
preclinical rodent model of PD. These findings provide a strong rationale
for the development of OGA inhibitors as disease-modifying agents
in both tauopathies and α-synucleinopathies. Since tau and α-synuclein
pathologies frequently co-exist in neurodegenerative diseases, OGA
inhibitors represent unique, multimodal drug candidates for further
clinical development.
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