Hepatocyte Transplantation for Liver Based Metabolic Disease

肝细胞移植治疗肝脏代谢疾病

• 批准号: 9762098
• 负责人: Ira J. Fox
• 金额: $ 95.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762098
• 关键词: Acute; Adolescent; Adult; Allografting; Amino Acids; Ammonia; Animal Model; Animals; Autologous; Bilirubin; Biological Assay; Biology; Blood; Carbon Dioxide; Cell Transplantation; Cell Transplants; Cells; Child; Clinic; Clinical; Development; Diagnosis; Diet; Disease; Disease model; Engraftment; Enrollment; Event; FDA approved; Fibroblasts; Gene Delivery; Generations; Goals; Graft Rejection; Hepatic; Hepatocyte; Hepatocyte transplantation; Immune; Immunologic Monitoring; Immunology procedure; Immunosuppression; Incidence; Intestines; Isomerism; Isotopes; Kidney; Laboratories; Liver; Liver diseases; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Monitor; Motivation; Neonatal Screening; Neurologic; Neurologic Dysfunctions; Neurologic Symptoms; Oral; Organ Transplantation; Palate; Pathologic Processes; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Phenylalanine Hydroxylase; Phenylketonurias; Pilot Projects; Process; Radiation; Reporting; Risk; Safety; Solid; Stem cells; Stimulus; System; T-Lymphocyte; TNFSF5 gene; Techniques; Technology; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; base; carbon skeleton; conditioning; executive function; experience; experimental study; fatty acid oxidation; gene transplantation for gene therapy; graft function; immunoreactivity; in vivo; indexing; induced pluripotent stem cell; innovation; liver transplantation; minimally invasive; neuropsychiatry; non-invasive monitor; nonhuman primate; novel; organic acid; oxidation; parenteral administration; patient population; population based; standard measure; success; targeted treatment; vector; young adult

Transplantation of isolated parenchymal cells has great promise as a minimally invasive therapy and partial success has been reported for several rare metabolic liver diseases. Major limitations to the technique include an inability to transplant an adequate mass of donor hepatocytes, and lack of a sensitive enough technology to monitor the status of transplanted cells. This proposal includes several major innovations in understanding hepatocyte transplant biology and optimizing its application. In animal models liver-directed radiation facilitates repopulation of the native liver by transplanted hepatocytes. Unfortunately, the standard clinical and laboratory signs that identify rejection in solid organ transplantation are not useful in recipients of cell transplants, and the sensitivity of functional changes following hepatocyte transplant is inadequate to diagnose rejection before damage to the allograft is irreversible. The availability of assays that would allow non-invasive monitoring of graft function and assessment of rejection risk would facilitate more rational management of patients following hepatocyte transplantation. As diseases targeted for treatment by hepatocyte transplantation are rare, and most reports involve anecdotal experience in a diverse patient population, we will transplant patients with phenylketonuria (PKU), a disease with an incidence that will make adequate patient enrollment possible. Phenylalanine hydroxylase (PAH) deficiency, traditionally known as PKU was the original motivation for population-based newborn screening. However, standard dietary management strategies have failed in older adolescents and adults due to difficulty in adhering to diet, leading to diminished executive function, and other neurologic and neuropsychiatric problems. The proposal has three specific aims. Aim 1 is to confirm the safety of liver-directed radiation conditioning and document 5-10% replacement of host hepatocytes by donor hepatocytes. We hypothesize that use of multiple donors and pre-transplant hepatic radiation conditioning will lead to competitive repopulation of the host liver and clinical correction of PAH deficiency in patients with PKU, a model disease for treatment of liver-based metabolic diseases. Aim 2 is to identify graft rejection by immunologic monitoring and to successfully treat it before the process is irreversible. We hypothesize that monitoring rejection risk by a proven assay of donor-specific T cell immune reactivity can be used to assess the adequacy of immune suppression following cell transplantation. Aim 3 is to determine the extent to which use of real-time measures of donor hepatocyte function, rather than use of surrogates, will allow assessment of graft function after hepatocyte transplantation. We hypothesize that isotopic Phe turnover studies in PKU patients can more effectively measure changes in Phe metabolism than standard measures. These results will be important for the possible transplantation of gene edited autologous or stem cell-derived hepatocytes. Delivery of gene editing vectors ex vivo to hepatocytes is significantly more efficient than in vivo delivery, and is even more efficient in patient-derived fibroblasts that would later be converted to iPS-derived hepatocytes.

分离的实质细胞的移植具有微创疗法和部分的巨大希望 据报道，几种罕见的代谢肝疾病的成功。该技术的主要限制包括 无法移植足够的供体肝细胞，并且缺乏足够敏感的技术来 监视移植细胞的状态。该建议包括一些理解的主要创新 肝细胞移植生物学并优化其应用。在动物模型中，肝导向辐射促进 通过移植的肝细胞对天然肝脏的重生。不幸的是，标准的临床和实验室 识别固体器官移植中排斥反应的迹象在细胞移植的接受者中没有用， 肝细胞移植后功能变化的敏感性不足以诊断排斥之前 对同种异体移植的损害是不可逆的。可以无创监视的测定法 移植功能和拒绝风险的评估将有助于对患者的更多合理管理 肝细胞移植。由于肝细胞移植针对治疗的疾病很少，而且 大多数报告都涉及各种患者人群的轶事经验，我们将移植患者 苯酮尿症（PKU），这种发病率将使患者入学到可能。 传统上称为PKU的苯丙氨酸羟化酶（PAH）缺乏是原始的动机 基于人群的新生儿筛查。但是，标准的饮食管理策略在较老的 青少年和成年人由于难以遵守饮食而导致执行功能降低，其他 神经系统和神经精神病学问题。该提案具有三个具体目标。目标1是确认安全 供体肝脏定向的辐射调节和文件5-10％替换供体供体肝细胞 肝细胞。我们假设使用多个捐赠者和移植前的肝辐射调节将 导致宿主肝脏的竞争重生和PKU患者PAH缺乏症的临床校正， 一种用于治疗肝脏代谢疾病的模型疾病。目标2是通过 免疫监测并在过程不可逆之前成功治疗。我们假设这一点 通过对供体特异性T细胞免疫反应性的经过验证的测定来监测排斥风险，可用于评估 细胞移植后免疫抑制的充分性。目标3是确定多大程度的程度 使用供体肝细胞功能的实时度量，而不是使用代孕，将允许评估 肝细胞移植后的移植功能。我们假设PKU中的同位素PHE更新研究 与标准措施相比，患者可以更有效地测量PHE代谢的变化。这些结果将会 对于可能移植基因编辑的自体或干细胞衍生的肝细胞很重要。 将基因编辑载体离体给肝细胞的递送比体内递送的效率要高得多，并且 在患者衍生的成纤维细胞中更有效，后来将转换为IPS衍生的肝细胞。