Human on a chip system to investigate genetic risk factors in Alzheimer's disease

Project Summary AbstractHesperos will construct and test microscale multi organ systems with recirculating blood and cerebral spinal fluid surrogates that will give insights to the responses of various Alzheimer s phenotypes to drugs as well as the influence of peripheral effects on AD progressionspecifically ApoE variantsWe seek to leverage DrMorgan s research on Alzheimer s and aging combine it with DrsShuler and Hickman s research on human on a chip systems to better understand the disease and its mechanism of action and to test efficacy and toxic side effects of treatmentsWe will investigate both small molecules and biologicson human organ modules in the same multi organ system using iPSC derived non diseasedNDand Alzheimer s phenotypesA preclinical model that can accurately predict human response should not only lead to better decisions on which Alzheimer s treatment to take into human clinical trialsbut also for personalized medicine applicationsBy eventually comparing acute to chronic effectsthe model will enable prediction of clinical trial success using pharmacodynamicPDmodels to inform clinical disease trials from preclinical studiesCurrent human based in vitro toxicity studies have the limited capacity to predict functional changes that have been the demise of many potential therapeuticsWe have previously constructed platforms demonstrating the integration of multiple organ mimics for acute responses and will build upon that technologyIn this Phase I proposal we will build aorgan system composed of cortical neuronal components to utilize long term potentiationLTPas a functional readoutwhich will be separated by a functional blood brain barrierBBBfrom a liver modelThe liver will result in a model with not only parental drugs but metabolites in the blood and the BBB will model the penetration of the drug and its metabolites into the brainWe will use isogenic methods to introduce the APP mutation into iPSCs and screen and select for ApoEand ApoEvariants to test in the system vscontrolThe effect of mutation and variant in both neurons and liver will give insight to peripheral as opposed to CNS effectsDevelopment of a low costeasy to use multi organ system to assay drugs for AD would facilitate widespread usage and maximize the benefit to the drug development community as well as for efficacy and toxicological evaluations for patient specific treatmentThe integrated use of these pre clinical test systems and PBPK PD models provides a powerful tool for evaluating the dynamic interaction between drugsaging biological system and disease and will facilitate rationale drug development and clinical trial designOur team contains all of the skill sets to achieve the goals on the grantIn Phase IIwe will expand our experiments from acute to chronic and then extend this to AD patient specific samples for personalized medicine applications Project NarrativeHesperos will construct and test microscale multi organ systems with recirculating blood and cerebral spinal fluid surrogates to give insights to the responses of various Alzheimer s phenotypes to drugs and chemicalsWe will compare AD disease models as well as ApoE variants to healthy neurons using cognitive function analogsDevelopment of a low costeasy to use system to assay drugs for AD would maximize the benefit to the drug development community and patients as well as improve efficacy and toxicological evaluations for patient specific treatments