2. Academic Validation
  3. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease

The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease

  • Sci Transl Med. 2023 Jan 18;15(679):eabp9352. doi: 10.1126/scitranslmed.abp9352.
Senthilkumar S Karuppagounder 1 2,  Hu Wang 1 2,  Terence Kelly 3,  Roger Rush 3,  Richard Nguyen 1,  Shivani Bisen 4,  Yoko Yamashita 4,  Nicholas Sloan 4,  Brianna Dang 4,  Alexander Sigmon 4,  Hyeun Woo Lee 4,  Shirley Marino Lee 4,  Leslie Watkins 2 4,  Erica Kim 2,  Saurav Brahmachari 1 2,  Manoj Kumar 1,  Milton H Werner 3,  Ted M Dawson 1 2 5 6,  Valina L Dawson 1 2 5 6
Affiliations

Affiliations

  • 1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3 Inhibikase Therapeutics Inc., Atlanta, GA 30339, USA.
  • 4 Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 5 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 6 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
PMID: 36652533 DOI: 10.1126/scitranslmed.abp9352
Abstract

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 α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

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