LPL-Deficient Cats-A Quantitative Model of Gene Delivery

LPL 缺陷猫——基因传递的定量模型

• 批准号: 7871436
• 负责人: PHILIP Richard VULLIET
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871436
• 关键词: Adult; Adverse reactions; Affect; Allogenic; Animal Model; Animals; Behavior; Binding; Blood Circulation; Bone Marrow; Bone Marrow Stem Cell; Breeding; Cell Count; Cell Therapy; Cells; Chemicals; Chylomicrons; Clinical Trials Design; Data; Defect; Disease; Dose; Drug or chemical Tissue Distribution; Endothelial Cells; Engraftment; Enzymes; Failure to Thrive; Felis catus; Fibrosis; Gene Delivery; Human; Hydrolysis; Immune response; Immunosuppressive Agents; Injection of therapeutic agent; Intravenous; Lipids; Lipoproteins; Location; Low Dose Radiation; Measures; Memory Loss; Mesenchymal; Metabolic; Metabolic Diseases; Methods; Modeling; Molecular; Monitor; Mutation; Pancreatitis; Patients; Peritoneal; Plasma; Population; Proteins; Protocols documentation; Quantitative Evaluations; Radiation; Reaction Time; Reporting; Route; Site; Stem cells; Stromal Cells; Techniques; Teratoma; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Treatment Protocols; Triglycerides; Xanthomas; chemotherapeutic agent; conditioning; design; improved; lipid metabolism; lipoprotein lipase; novel; public health relevance; research study; response; safety study; stem cell technology; stem cell therapy

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.

描述（由申请人提供）：定量数据对于设计有效的干细胞治疗方案至关重要。我们已经确定了一种新的动物模型，脂蛋白脂肪酶缺陷（LPL-/-）猫，这将提供这一重要的数据。脂蛋白脂酶是调节血浆脂蛋白分解和脂质代谢的关键酶。脂蛋白缺乏症是一种严重的常染色体隐性遗传疾病，其特征是严重的乳糜微粒血症、胰腺炎、发疹性黄瘤、视网膜脂血症、记忆力丧失和发育不良。这种疾病在人类中被称为“家族性乳糜微粒血症”。LPL-/-猫具有相同的突变，不能水解乳糜微粒，导致其血脂谱（PLP）的相同畸变。该项目将确定表达活性LPL的同种异体间充质基质细胞（MSC）是否会纠正这种遗传缺陷。初步研究表明，同种异体骨髓间充质干细胞合成LPL和短暂纠正这种LPL缺乏。首先，我们将量化LPL-/-猫中增加和多次静脉注射LPL +/+ MSC的效果（目的I）。我们预期供体间充质干细胞将植入宿主骨髓并分泌活性脂蛋白脂酶。一旦进入循环，LPL结合到内皮细胞上的特定位点，水解乳糜微粒并纠正这种代谢缺陷。循环乳糜微粒和甘油三酯的减少很容易监测。还将研究影响植入的潜在因素，例如各种给药途径、用辐射预处理受体猫和注射预分化的MSC（目的II）。由于易于测量治疗效果，LPL缺陷猫提供了一个极好的机会来证明同种异体MSC纠正这种遗传缺陷的能力。这种独特的模型允许直接定量分析治疗反应，同时测量远交动物群体中MSC的存在。该项目将提供重要的剂量-反应和时间-过程数据，确定注射的MSC的组织分布，并提供其他必要的细胞动力学数据。这些信息将直接转化为类似和其他代谢紊乱的人类患者的临床试验设计。 公共卫生相关性：本计画将探讨异基因骨髓干细胞对远系猫的遗传性代谢错误的矫正潜力。我们将从脂蛋白脂酶活性正常的猫中分离出成体骨髓干细胞（MSCs），并将其注射到脂蛋白脂酶活性缺乏的猫体内。在这个项目中，我们将研究几种不同的方法来增加这种反应和方法，以提高这些细胞的植入和延长这些治疗效果。