The devastation of Alzheimer's dementia costs $100 billion today and will economically cripple American health care if not controlled in the next decade. Pathology and genetic studies indicate the accumulation of the Aa peptide as a major precipitating factor in the disease. Multiple strategies using traditional small molecule drugs to arrest this accumulation are being investigated, but, thus far, success remains elusive. One; problem is that systemic application of many agents have unintended consequences outside the brain. Even the anti-Aa vaccines had to be halted due to unforeseen, serious adverse events. This application proposes a relatively new approach to lowering brain Aa by exploiting gene therapy to enhance the clearance and reduce the production of Aa. The approach will inject recombinant acieno-associated viral vectors (rAAV), known to safely result in stable neuronal expression of transduced genes, into APP+P81 transgenic mice, which reliably deposit a amyloid and develop learning and memory deficits. rAAV vectors transferring proteases to degrade Aa or transferring inhibitory RNA constructs against enzymes producing Aa will be injected into the hippocampus and cerebral cortex. Their efficacy and safety of these vectors will be tested in young mice, to evaluate their capacity as prophylactic treatments and in older mice to estimate their potential utility as therapeutics. Additionally, we will investigate multiple methods for maximizing the distribution of transferred genes throughout the nervous system. The rAAV construct with therapeutic efficacy, optimal safety and broad distribution will be selected for further development as a treatment for Alzheimer's. The outcome of these studies will, hopefully, be a novel gene therapeutic approach to dismantle the catastrophe of Alzheimer's dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG025509-02S1
Application #
7288141
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buckholtz, Neil
Project Start
2005-09-15
Project End
2010-05-31
Budget Start
2006-09-30
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$30,760
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Selenica, Maj-Linda B; Reid, Patrick; Pena, Gabriela et al. (2016) Adeno associated viral-mediated intraosseous labeling of bone marrow derived cells for CNS tracking. J Immunol Methods 432:51-6
Nash, Kevin R; Lee, Daniel C; Hunt Jr, Jerry B et al. (2013) Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol Aging 34:1540-8
Carty, Nikisha; Nash, Kevin R; Brownlow, Milene et al. (2013) Intracranial injection of AAV expressing NEP but not IDE reduces amyloid pathology in APP+PS1 transgenic mice. PLoS One 8:e59626
Morgan, D (2011) Immunotherapy for Alzheimer's disease. J Intern Med 269:54-63
Carty, Nikisha; Lee, Daniel; Dickey, Chad et al. (2010) Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain. J Neurosci Methods 194:144-53
Lebson, Lori; Nash, Kevin; Kamath, Siddharth et al. (2010) Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30:9651-8
Lord, Anna; Englund, Hillevi; Söderberg, Linda et al. (2009) Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice. FEBS J 276:995-1006
Morgan, Dave; Landreth, Gary; Bickford, Paula (2009) The promise and perils of an Alzheimer disease vaccine: a video debate. J Neuroimmune Pharmacol 4:1-3
Morgan, Dave (2009) The role of microglia in antibody-mediated clearance of amyloid-beta from the brain. CNS Neurol Disord Drug Targets 8:7-15
Morgan, Dave; Munireddy, Sanjay; Alamed, Jennifer et al. (2008) Apparent behavioral benefits of tau overexpression in P301L tau transgenic mice. J Alzheimers Dis 15:605-14

Showing the most recent 10 out of 17 publications