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.

分离的实质细胞移植作为一种微创治疗和局部移植有很大的前景