Objective: IkT-148009 is a potent selective inhibitor of non-receptor Abelson Tyrosine Kinases (c-Abl kinases).  Our recent analysis of post-mortem brain tissue from patients with Multiple System Atrophy (1) demonstrated that c-Abl activation may be an important component of the neurodegenerative disease process in these patients.  In this study we intend to assess the therapeutic potential of IkT-148009 to alter the course of MSA in mouse models of the disease.

Background: Multiple System Atrophy (MSA) is a rapidly progressive orphan disease affecting the central and autonomic nervous systems. MSA is characterized by pathological alpha-synuclein aggregation, which form so-called gliocytoplasmic inclusions, or GCIs, in oligodendroglial cells that lead to neurodegeneration with rapid disease progression, usually ending in death within 8 years of diagnosis.  We have recently described the origin of alpha-synuclein aggregate pathology, characterizing the role of c-Abl activation in the initiation and progression of the disease (2) . This prompted us to evaluate the role of c-Abl activation in MSA and therapeutic treatment of MSA in model organisms.

Method: Two different models were created.  One used the transgenic Prion-Like Promoter (PLP) model, which directs alpha-synuclein expression primarily in oligodendroglial cells. In the PLP model, expression of alpha-synuclein leading to GCIs occurs continuously.   A second model uses the AAV-directed Oligo-001 vector (1).  At the point when significant functional deficit was observed, once daily oral administration was begun with IkT-148009 to test whether IkT-148009 could have a prophylactic or therapeutic impact on disease.

Results: As of this writing, these experiments are ongoing, but interim analysis demonstrates that IkT-148009 protected against hind limb slippage errors measured by the notched beam test in both male and female mice in the PLP model. In the therapeutic AAV model, the ability of IkT-148009 to halt disease progression and/or to reverse functional loss by various behavioral and biochemical measures will be presented.

Conclusion: As of this writing, ongoing experiments have suggested a possible benefit for c-Abl inhibition as an interventional therapy for MSA.  Detailed results will clarify the role of c-Abl activation in the disease process and the potential benefit of c-Abl inhibition as a disease-modifying therapy in the model organism.

References: 1) DOI: 10.1016/j.nbd.2020.105184
2) DOI: 10.1126/scitranslmed.abp9352

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-the-therapeutic-potential-of-c-abl-inhibition-in-multiple-system-atrophy/