Swine model of monogenic diabetes with potential implications for T1D, T2D, and double diabetes

Diabetes mellitusDMis a metabolic ailment caused by inadequate production or utilization of insulinfeatured by excessive amounts of glucose in the bloodThe incidence of diabetes has been rising globallyDiabetes is often diagnosed lateafter the insulin producing pancreaticcells have already undergone severe damageleading to multi organ complicationsTo avoid these complicationspreventionearly diagnosistimely interventionand development of new drugs are necessaryAnimal modelsparticularly rodentshave been established for the study of diabetes and diabetic complicationsand have helped to identify drug targets and test new drugs for DMHoweverrodent physiology vastly differs from humanhencerodent models cannot precisely mimic human diabetesConverselyphysiology and glucose metabolism of the pig closely resemble that of the humanproving the pig a suitable model system to study human diabetesparticularly prediabetic metabolic changesEarly detection of these metabolic changes is vital for timely interventionsThe two most common diabetestypeanddiabetesT D and T Dare caused by different environmental insults and multiple gene defects that are difficult to simulate in animal modelsOpportunelysingle gene defects of diabetes that are relatively easier to model in animals existFor examplea recently reported point mutation in the sirtuinSIRTgene causes autoimmune mediated pancreaticcell destruction characteristic of T D in human patientsTo that endthe overall goal of this project is to create genome edited swine with point mutations in the SIRTgene that will simulate important features of human T Dincluding severe insulin deficiency and autoimmune mediated pancreaticcell destructionThis goal will be achieved by engineering SIRT LP mutations using CRISPR mediated homology dependent repairHDRin Ossabaw fibroblastsfrom which founder pigs with the specific single gene mutation will be generated through cloningThese gene edited founder pigs will be characterized by clinical and pathological examinationsIntroduction of SIRT LP mutation into the Ossabaw genome will exhibit typical clinicopathological features of T Dparticularly its hallmark autoimmune destruction of pancreaticcellsunlike any current animal model of human diabetesOwing to the natural propensity of Ossabaw pigs to develop T Dthe edited pig also enables modeling large animal model of double diabetesDDafter diet inductionThe SIRT LP model of T D will open new avenues for testing and developing breakthrough therapies for human use and may shift the existing clinical paradigm from frequent exogenous insulin injection towards novel correctiveor even curativeimmune therapies This project will fund the development of monogenic autoimmune mediated swine model of typediabetesT DWe use gene editing technology to introduce SIRT LP mutation into swine genomewhich cause T D in humanWe propose that this unique large animal model mimics the human conditionand help accelerate the development of new diagnostic biomarkers and novel therapeutic targets for T D that may lead to cure