1. Preclinical and Clinical Studies of p38α MAP kinase inhibition to Treat Basal Forebrain Cholinergic Dysfunction and Degeneration
- Author
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Ursula Germann, Cynthia Bleiwas, John Alam, Dun-Sheng Yang, Balapal S. Basavarajappa, Sandeep Malampati, John Harrison, Kelly Blackburn, Afina W. Lemstra, Paul Maruff, Monika Plawik, Shivakumar Subbanna, Amanda Gardner, Niels D. Prins, Charlotte E. Teunissen, Ralph A. Nixon, Ying Jiang, John F. Smiley, Anna Pensalfini, Stephen N. Gomperts, Sandipkumar Darji, Philip Scheltens, James Peddy, and Philip Stavrides
- Subjects
Basal forebrain ,biology ,business.industry ,Mitogen-activated protein kinase ,biology.protein ,Medicine ,Cholinergic ,Degeneration (medical) ,business ,Neuroscience - Abstract
The endosome-associated protein Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α kinase is a Rab-5 activator, we hypothesized that inhibition of this kinase held potential as an approach to treat diseases associated with BFCN loss. Herein we report that treatment with an oral small molecule p38α kinase inhibitor reversed pathological disease progression in the basal forebrain in a mouse model that develops BFCN degeneration. Further, the preclinical results were successfully translated to the clinic, with improvement of clinical outcomes associated with cholinergic function in a clinical study in dementia with Lewy bodies (DLB), a disease in which BFCN dysfunction and degeneration is the primary driver of disease expression. The findings both advances a novel approach to treating DLB and validates the translational platform that provided the mechanistic rationale for advancing that approach.
- Published
- 2021
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