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bioRxiv · 10.1101/2025.11.19.689275

Silmitasertib, an FDA-designated orphan CK2 Inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model

Pelzel, R.·Herbst, M. A.·Rozema, N. B.·Solem, M. A.·Gomez-Pastor, R.
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Abstract

Huntingtons disease (HD) is a devastating autosomal dominant neurodegenerative disease that manifests with progressive motor, cognitive, and psychological impairments. HD is caused by a polyQ (CAG) repeat expansion in the huntingtin (HTT) gene, leading to the misfolding and aggregation of mutant HTT protein (mHTT) and the preferential degeneration of the striatum. Previously in our lab, we identified Protein Kinase CK2 as an important kinase involved in the pathophysiology of HD. Specifically, the alpha prime catalytic subunit of CK2 (CK2) is upregulated in HD, and genetic depletion of CK2 in HD mice results in improved motor behavior, decreased mutant Htt aggregation, and improved neuronal function. Silmitasertib (CX-4945) is an FDA designated orphan drug that inhibits CK2. This study aims to investigate whether CX-4945 treatment ameliorates HD pathology. We treated prodromal and late symptomatic HD mice, and used a variety of immunohistochemical, biochemical, physiological and behavioral approaches. We found that CX-4945 presented benefits in the amelioration of HD pathophysiology in both treated groups. Importantly, we found CX-4945 decreased mHtt aggregation, increased DARPP-32 expression and excitatory synapse density, restored homeostatic astrocyte phenotypes and ameliorated neuroinflammation and microgliosis, altogether resulting in improved motor behavior. These results support CX-4945 as a strong candidate for a targeted therapy to treat HD.

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Pelzel, R., Herbst, M. A., Rozema, N. B., Solem, M. A., Gomez-Pastor, R.. 2025-11-20. Silmitasertib, an FDA-designated orphan CK2 Inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model. https://doi.org/10.1101/2025.11.19.689275

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