Fyn Inhibition by AZD0530 for Alzheimers Disease

Summary

Principal Investigator: Christopher H van Dyck
Abstract: DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative condition with a massive health burden, but no therapeutic option to slow or halt progression. It is estimated that up to 14 million Americans will suffer from AD by 2050, which, apart from the human cost, could have a catastrophic effect on our health care system and the broader economy. This application aims to assess the potential therapeutic benefit of AZD0530 (Saracatinib) for AD. AZD0530 is a selective inhibitor of Src family kinases, and has been developed primarily for the treatment of cancer. However, our data show that Fyn kinase, a member of the Src family kinases, also plays a fundamental role in the pathogenesis of AD. Multiple studies implicate Fyn kinase in the synaptic pathophysiology of AD, with links to both Ass and Tau pathology. For transgenic AD mice, genetic removal of Fyn kinase alleviates, and overexpression of Fyn exacerbates, the impairment of synaptic density and spatial memory. The A beta peptide is thought to trigger AD. Our work, confirmed and extended by others, showed that Cellular Prion Protein (PrPC) acts as a toxic Ass oligomer receptor. Downstream signaling from the A beta-PrPC complex is of major interest, as it might provide for a selective therapeutic target in AD. Recently, engagement of PrPC by A beta was found to activate Fyn kinase, initiating a detrimental signaling cascade with synaptic dysfunction. These data provide a direct mechanistic link between A beta and Fyn kinase in AD. In addition, Fyn kinase interacts directly with Tau, and the synaptic function of Fyn requires dendritic Tau. We hypothesize that blocking Fyn kinase is an effective therapeutic strategy in AD. AZD0530 safely inhibits Src family kinases, including Fyn, with high potency in humans. This application will validate the predicted benefit of AZD0530 in a mouse model of AD while measuring pharmacodynamic parameters, and initiate clinical trials. A Phase 1b trial will determine cerebrospinal fluid drug levels in AZD0530-treated human AD subjects and confirm safety and tolerability. Achievement of milestones for the preclinical and clinical Phase 1 studies will support the initiation of a Phase 2a proof-of concept clinical trial. A total of 159 patients will be studied in a 12-month, double-blind randomized placebo-controlled trial of AZD0530 in mild Alzheimer's disease. The primary outcome measures will include the slowing of a decline in regional brain glucose metabolism as measured by 18F-FDG PET imaging (a validated surrogate marker for clinical progression in AD), as well as assessments of safety and tolerability. Secondary outcomes will include standard clinical efficacy measures, rate of change in MRI volumes, and CSF total Tau and phospho-Tau. The goal of this project is to provide evidence in support of a multi-center Phase 3 trial of AZD0530 in AD.
Funding Period: 2013-06-18 - 2014-05-31
more information: NIH RePORT

Research Grants

  1. FRONTOTEMPORAL DEMENTIA: GENES, IMAGES, AND EMOTIONS
    Bruce L Miller; Fiscal Year: 2013
  2. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
  3. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
  4. Alzheimer's Disease Research Center
    Mary Sano; Fiscal Year: 2013
  5. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  7. History of Alzheimer predisposes children to amyloid beta-related hypometabolism
    Lisa Mosconi; Fiscal Year: 2013
  8. Aging Well, Sleeping Efficiently
    Timothy H Monk; Fiscal Year: 2013
  9. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013
  10. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013

Detail Information

Research Grants30

  1. FRONTOTEMPORAL DEMENTIA: GENES, IMAGES, AND EMOTIONS
    Bruce L Miller; Fiscal Year: 2013
    ..abstract_text> ..
  2. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  3. ALZHEIMER DISEASE RESEARCH CENTER
    HELENA CHANG CHUI; Fiscal Year: 2013
    ..abstract_text> ..
  4. Alzheimer's Disease Research Center
    Mary Sano; Fiscal Year: 2013
    ..abstract_text> ..
  5. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
    ..Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research. ..
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  7. History of Alzheimer predisposes children to amyloid beta-related hypometabolism
    Lisa Mosconi; Fiscal Year: 2013
    ..This project will test the hypothesis that hypometabolism in children of AD-mothers is due to a combination of systemically increased oxidative stress from the mitochondria and increasing amyloid-beta deposition. ..
  8. Aging Well, Sleeping Efficiently
    Timothy H Monk; Fiscal Year: 2013
    ..This Program Project will significantly advance our understanding of insomnia and its treatment in older adults. ..
  9. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013
    ..HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it. ..
  10. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013
    ..The ADRC will also continue to be a training platform for young investigators. ..
  11. Alzheimer's Disease Research Center
    Thomas J Montine; Fiscal Year: 2013
    ..Montine;Project 2: Therapeutic Effects of Intra-Nasal Insulin Detemir, Dr. Suzanne Craft;Project 3: Modulation of A peptide accumulation and neuron damage in vivo with adult bone marrow transplants, Dr. C. Dirk Keene. ..
  12. PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION
    Sundeep Khosla; Fiscal Year: 2013
    ..Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population. ..
  13. Behaviors on Surveys and in the Economy: HRS and Beyond
    Robert J Willis; Fiscal Year: 2013
    ..abstract_text> ..
  14. UCLA Alzheimer's Disease Research Center
    David B Teplow; Fiscal Year: 2013
    ..Innovations in advancing research are proposed in each Core of this proposal. Each core has responded to criticisms and recommendations from the 2008 review in this renewal application. ..
  15. IL-13 and IL-17 dynamics in the asthmatic airway
    Dean Sheppard; Fiscal Year: 2013
    ..RELEVANCE: Epithelial cells line the airways and play an important role in asthma. Micro-RNAs regulate gene expression. We will identify the nature, causes and consequences of changes in airway epithelial cell micro-RNAs in asthma. ..
  16. Alzheimer's Disease Research Center
    Oscar L Lopez; Fiscal Year: 2013
    ..Alzheimer's centers such as the one in Pittsburgh play a critical role in the nation's struggle to: 1) care for those currently afflicted;2) improve diagnosis and treatment;and 3) find a means of prevention. ..
  17. Center for Novel Therapeutics for HIV-Associated Cognitive Disorders
    Justin C McArthur; Fiscal Year: 2013
    ..5. To identify and validate surrogate biomarkers based on proteomics and lipomics. ..
  18. Assessment of Biomarkers and Behavior in a Transgenic Rat Model of AD
    EDMOND HUATUNG TENG; Fiscal Year: 2013
    ....
  19. Sex-specific Risk for Vascular Dysfunction and Cognitive Decline
    Virginia M Miller; Fiscal Year: 2013
    ..These studies will identify which women might benefit from early treatments to sustain cognitive health across their life transitions. ..