Gene Replacement Therapy in Induced Pluripotent Stem (iPS) Cells for Treatment of

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The UAB Stem Cell Institute, the UAB BioMatrix Engineering and Regenerative Medicine (BERM) Center, and the UAB Hematopoietic Stem Cell Processing Facility will collaborate in a program to develop gene replacement therapy using induced pluripotent stem (iPS) cells for treatment of sickle cell disease. The program consists of two projects and two cores. In Project 1 (Human iPS Cells for Sickle Gene Replacement), Dr. Townes proposes to translate recent success in correcting sickle cell disease in a humanized sickle mouse model into human cells. The specific aims of the project are to: (1) produce human iPS cells from skin biopsy samples of patients with sickle cell disease (2) to correct the sickle mutation in iPS cells derived from patients (3) and to differentiate corrected iPS cells into transplantable hematopoietic stem cells that produce normal erythroid cells. In Project 2 (Canine iPS Cells For Pyruvate Kinase Gene Replacement), Dr. Clint Lothrop proposes to correct a large animal model of hereditary anemia (pyruvate kinase deficiency in dogs) by gene replacement in canine iPS cells. The specific aims of this project are: (1) to produce canine iPS cells from skin biopsy samples of dogs with hereditary pyruvate kinase (PK) deficiency (2) to correct the PK mutation in iPS cells derived from PK animals (3) and to differentiate corrected iPS cells into hematopoietic stem cells that correct the disease after transplantation. These large animal studies will be crucial to prove the efficacy and safety of iPS based gene therapy for hereditary anemias. Two cores will facilitate the studies described above. Dr. Timothy Wick will direct a Bioreactor Core for the large-scale culture and differentiation of iPS cells into hematopoietic progenitors, and Dr. Larry Lamb will direct a Hematopoietic Cell Processing Core for the purification of hematopoietic progenitors from corrected iPS cells. These two cores will be crucial to the translation of this work to human clinical trials.