Pharmacodynamic endpoints for MW151, a novel small molecule attenuator of dysregulated proinflammatory cytokine production

2016  -  KY, USA

Grantees

Dr. David Braun

Organizations

University of Kentucky

Supervising Advisor: Dr. Linda Van Edlik

Project summary:

Alzheimer’s disease (AD) is one of the largest global public health crises facing us today, and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent, cure, or slow the progression of disease, and new therapeutic strategies are urgently needed. We are developing MW151, a small molecule AD drug candidate that targets neuroinflammation, a pathological condition recently recognized as a key contributor to AD-associated neurodegeneration and cognitive decline. Dysregulated proinflammatory cytokine (PIC) production is a component of neuroinflammation that drives the progression of diverse degenerative CNS disorders. Data from epidemiological, clinical and preclinical animal model studies converge on the attenuation of PIC overproduction as a potential disease-modifying therapeutic approach to AD.

MW151 is a novel, CNS-penetrant, orally bioavailable, small molecule drug candidate that selectively attenuates disease-induced PIC up-regulation in the brain. Among the various animal models of CNS disorders where MW151 has demonstrated efficacy are two distinct AD mouse models. In both models, amyloid β (Aβ)-induced increases in PICs were restored to normal and the associated synaptic deficits and cognitive decline were attenuated by MW151 treatment. MW151 is currently in IND-enabling preclinical development as a promising non-amyloid targeted AD drug candidate.

In the proposed project, we will measure a set of preclinical PD endpoints that reflect drug engagement of the targeted pathway in order to determine their potential for translation to future human AD clinical trials.