2016 Advisor Fellow

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 â (Aâ)-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. A major hurdle in clinical development of non-amyloid targeted AD drugs is the lack of clinical endpoints for the direct monitoring of pharmacodynamic (PD) effects during clinical trials. To identify such PD endpoints, we propose to use the well-characterized APPÄNLh/ÄNLh x PS1P264L/P264L knock-in (KI) mouse model, which develops age-related progressive AD pathology (amyloid plaques, synaptic dysfunction, cognitive impairment), as well as prominent dysregulated PIC production that contributes to the synaptic and behavioral deficits. MW151 intervention restores the PIC levels towards normal and improves neurologic outcomes. This mouse model uses endogenous promoters to drive the production of humanized Aâ, avoiding the common approach of Aâ overproduction, allowing for a progressive increase in pathophysiology progression markers with chronological age. MW151 intervention at disease presentation stage or earlier at a preventive stage improves disease-relevant outcomes. 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. Aim 1: In a mouse model of AD pathology progression, determine the effects of MW151 on selected endpoints related to dysregulated PIC status. The effect of MW151 on the following endpoints will be measured: (a) PICs in serum, cerebrospinal fluid (CSF), and in brain tissue (as a confirmatory test), (b) cerebral blood flow by arterial spin labeling, and (c) brain metabolic changes by proton magnetic resonance spectroscopy. Biofluid and imaging endpoints were selected for their potential to be translated to human clinical tests. Aim 1 milestone: Identify at least one translatable PD PIC- or neuroimaging marker whose change will correlate with MW151 action in the brain. Aim 2: Confirm that the effects of MW151 on the neuroinflammatory-related PD endpoints correlate with its effects on synaptic and cognitive endpoints. We will examine the association of the MW151 intervention-induced changes in the translatable endpoints from Aim 1 with its known effects on selected synaptic protein levels in brain tissue (as a positive control confirmatory test) and on cognitive performance in two standard behavioral tests (radial arm water maze and novel object recognition). The results will inform us of the potential for the neuroinflammation endpoints to reflect the link between MW151 pharmacological mechanism of action and efficacy. Aim 2 milestone: The changes in the translatable neuroimaging and fluid biospecimen endpoints in aim 1 are consistent with positive effects of MW151 treatment on synaptic and cognitive endpoints. Identification of translatable neuroinflammation-related endpoints that correlate with neuronal dysfunction endpoints will facilitate the selection of surrogate clinical endpoints for acceleration of the planned future AD clinical trials. Success will also, at the least, serve as a proof-of-concept for adding this clinically unexplored