LPL-Deficient Cats-A Quantitative Model of Gene Delivery

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DESCRIPTION (provided by applicant): Quantitative data are essential for the design of effective stem cell treatment protocols. We have identified a novel animal model, the lipoprotein lipase-deficient (LPL-/-) cat, that will provide this essential data. Lipoprotein lipase is a key enzyme regulating plasma lipoprotein breakdown and lipid metabolism. LPL-deficiency is a serious autosomal recessive disorder characterized by severe chylomicronemia, pancreatitis, eruptive xanthomata, lipemia retinalis, memory loss and failure to thrive. This disease is termed "familial chylomicronemia" in humans. LPL-/- cats share the identical mutation and cannot hydrolyze chylomicrons resulting in identical aberrations of their plasma lipid profile (PLP). This project will determine if allogeneic mesenchymal stromal cells (MSCs) expressing active LPL will correct this genetic defect. Preliminary studies demonstrate that allogeneic MSCs synthesize LPL and transiently correct this LPL deficiency. Initially, we will quantify the effects of increasing and multiple intravenous doses of LPL+/+ MSCs in LPL-/- cats (Aim I). We anticipate that donor MSCs will engraft the host's bone marrow and secrete active lipoprotein lipase. Once in circulation, LPL binds to specific sites on endothelial cells, hydrolyzes chylomicrons and corrects this metabolic defect. Decreases in circulating chylomicrons and triglycerides are easily monitored. Potential factors affecting engraftment, such as various routes of administration, pre-treatment of the recipient cat with radiation, and injection of pre-differentiated MSCs will also be investigated (Aim II). Because of the ease of measuring therapeutic effects, LPL-deficient cats offer an excellent opportunity to demonstrate the ability of allogeneic MSCs to correct this genetic defect. This unique model allows direct quantitative analyses of therapeutic responses while simultaneously measuring the presence of MSCs in an outbred animal population. This project will provide important dose-response and time- course data, identify tissue distribution of injected MSCs, and supply other essential cytokinetic data. This information will directly translate to the design of clinical trials in human patients with similar and other metabolic disorders. PUBLIC HEALTH RELEVANCE: This project will investigate the potential of allogeneic bone marrow stem cells to correct heritable metabolic errors in an out-bred strain of cats. We will isolate adult bone marrow stem cells (MSCs) from cats with normal lipoprotein lipase activity and inject them into cats lacking lipoprotein lipase activity. In this project we will investigate several different methods for increasing this response and methods to enhance engraftment of these cells and prolong these therapeutic effects.