Modulation of the Innate Immune Response by Fisetin Derivatives for the Treatment of AD

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42AI104034-03A1
Agency Tracking Number: R42AI104034
Amount: $1,499,999.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA15-270
Timeline
Solicitation Year: 2015
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-03-15
Award End Date (Contract End Date): 2018-07-19
Small Business Information
4050 SORRENTO VALLEY BLVD STE O, San Diego, CA, 92121-1425
DUNS: 146101196
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 PAMELA MAHER
 (858) 453-4100
 pmaher@salk.edu
Business Contact
 WILLIAM RASCHKE
Phone: (858) 450-2561
Email: braschke@virogenicsinc.com
Research Institution
 SALK INSTITUTE FOR BIOLOGICAL STUDIES
 10010 N TORREY PINES RD
LA JOLLA, CA, 92037-1002
 Domestic nonprofit research organization
Abstract
DESCRIPTION provided by applicant There are currently no drugs or other therapeutic interventions that can reverse or halt the progression of Alzheimerandapos s disease AD Age is by far the greatest risk factor for AD and it is known from studies in both mice and humans that neuroinflammation is increased with old age and to an even greater extent in AD Therefore a drug that could reduce neuroinflammation and at the same time be neuroprotective would have an excellent chance in the clinic To address this problem we have devised a drug discovery program based upon a unique set of phenotypic screens for the toxicities to cortical neurons that occur with old age in combination with assays of anti inflammatory activity Our initial studies using this approach led to the identification of a molecule that modulates neuroinflammation in ways that are beneficial for altering AD progression This is the flavonoid fisetin which our cell and animal studies have demonstrated inhibits multiple pro inflammatory pathways Fisetin a rare natural flavonoid was initially identified in the Maher laboratory as an orally active novel neuroprotective and cognition enhancing molecule Fisetin protects nerve cells from multiple toxic insults and is therapeutically active in rigorous rodent models for memory rabbit and mouse models for ischemic stroke mouse and fly models of Huntingtonandapos s disease and in transgenic AD mice A series of much more potent fisetin derivatives many of which maintain in vitro anti inflammatory activity was synthesized by SAR driven iterative chemistry Importantly the derivatives do not suffer from the intellectual property challenges of the natural product fisetin and are covered under several pending patents held by the Salk Institute From the derivatives synthesized we selected the best seven derivatives that maintain the biological activities of fisetin including its anti inflammatory activity and furthe screened them in multiple assays relevant to neuroinflammation In addition pharmacokinetic studies were done to identify the derivatives with the best oral bioavailability and brain penetrance Based on these studies the best two derivatives were then tested in a stringent reversal paradigm in old symptomatic AD mice where CMS was found to be effective at reversing the AD phenotype We now propose to advance CMS as a modulator of neuroinflammation and a clinical candidate for the treatment of AD Specifically we plan to Test CMS in a novel model of old age associated sporadic AD that accounts for of the cases looking at both behavioral and biochemical changes with a focus on neuroinflammation Identify the biological target s of CMS and Identify the key metabolites of CMS and conduct preliminary toxicology studies The overall goal of the research described in this application is to obtain sufficient information about CMS to limit the risk of the expensive formal toxicology study needed for IND approval as well as provide the necessary information to increase the efficiency of these studies PUBLIC HEALTH RELEVANCE Currently there are no drugs that can prevent slow or stop the progression of Alzheimerandapos s disease We propose to develop a novel compound that is both neuroprotective and able to harness the good aspects of the brainandapos s immune system in order to prevent the loss of brain function in Alzheimerandapos s disease If successful this approach could prove beneficial for the treatment not only of Alzheimerandapos s disease but also a number of other age related neurological disorders

* Information listed above is at the time of submission. *

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