A Humanized Swine Model for Alzheimer's Disease

PROJECT SUMMARY Alzheimer s disease AD affects million people worldwide costing $ billion yearly One in nine Americans over the age of have AD the th leading cause of death in the US Annually $ billion is spent to care for the million Americans with AD AD is the only cause of death in the top that cannot be prevented cured or slowed and without the development of treatments for AD it is expected that by there will be million Americans with AD costing $ trillion yearly Life expectancy following AD diagnosis is only years AD patients suffer from chronic neurodegeneration gradual loss of bodily functions and a poor quality of life Studying patients with early onset AD has elucidated many genes that play a role in AD including the critical role of the Amyloid Precursor Protein gene hAPP and the Microtubule Associated Protein Tau gene hMAPT To date models of AD have been largely developed in mice and no therapies developed in these models have proven effective in humans likely due to the large anatomical and physiological variation between human and rodent brains coupled with the failure of mice to develop the neurodegenerative processes and brain lesions seen in AD patients Compared to rodents swine have much greater genetic anatomic and physiological similarity to humans offering an opportunity to model a complex neuropathological disease in a large animal The large gyrencephalic brain of the pig is similar in size and structure to humans and a model of diffuse brain injury in swine shows AD like pathology with accumulation of amyloid beta A and Tau We propose to establish a swine model of AD allowing researchers to understand the biology of AD enable doctors to establish methods of early detection and ultimately lead to the identification of new therapies to prevent halt the progression of and reverse AD We will establish this model using our powerful and proprietary genetic engineering techniques to replace swine APP and MAPT genes with human AD associated alleles of these genes This will allow us to precisely model human AD in swine and develop therapeutics that could be pre clinically tested for safety and efficacy in our swine and moved directly to human clinical trials We will assess the resulting animals at months of age by magnetic resonance imaging to determine if they have suffered neurodegeneration by whole brain and hippocampal volume measurement as well as if amyloid plaques have formed or they display a pattern of abnormal brain metabolite concentrations consistent with AD patients PROJECT NARRATIVE Alzheimer s disease AD affects million people worldwide costing $ billion yearly and one in nine Americans over the age of have AD the th leading cause of death in the US Annually $ billion is spent to care for the million Americans with AD but without the development of treatments for AD it is expected that by there will be million Americans with AD costing $ trillion yearly Because animal models of AD have failed to reproduce the biology of the disease and no treatments that have been able to stop slow or prevent the disease have been developed using these models we propose to establish a swine model of AD allowing researchers to understand the biology of AD enable doctors to establish methods of early detection and ultimately lead to the identification of new therapies to prevent halt the progression of and reverse AD