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Published December 5, 2022 | Version v1
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The c-Abl inhibitor IkT-148009 therapeutically suppresses neurodegeneration in models of heritable and sporadic Parkinson's Disease

Creators

  • 1. Johns Hopkins Medicine
  • 2. Inhibikase Therapeutics (United States)

Description

Parkinson's Disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded a-synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson Tyrosine Kinase, or c-Abl, plays an essential role in the initiation and progression of a-synuclein pathology and initiates processes leading to the degeneration of dopaminergic and non-dopaminergic neurons. Given the essential role of c-Abl in the disease, a proprietary c-Abl inhibitor library was developed to identify potent, orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on pre-defined characteristics, leading to the discovery of IkT-148009. IkT-148009 is a selective, potent, brain-penetrant c-Abl inhibitor with a favorable toxicology profile that was analyzed for therapeutic potential in animal models of slowly progressive, a-synuclein-dependent disease. In models of both inherited and sporadic Parkinson's disease in the mouse, IkT-148009 suppressed c-Abl activation to baseline and substantially protected neurons from degeneration when administered therapeutically by once daily oral gavage beginning four weeks after disease initiation. Recovery of normal behavioral function in diseased mice occurred within 8 weeks of initiating treatment and occurred concomitantly with a substantial reduction of a-synuclein pathology in the brain. These disease-modifying outcomes in mice suggest IkT-148009 has the potential to be a disease-modifying therapy in human disease.

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Funding provided by: National Institute of Neurological Disorders and Stroke
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000065
Award Number: R44NS103695

Funding provided by: Michael J. Fox Foundation
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000864
Award Number: 13682

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