PhD Juan Novoa Rengifo
Research Project:
Generation of GMP-compliant immune evasive iPSC lines.
The utilization of human induced pluripotent stem cells (hiPSCs) for disease modeling and drug discovery is already a reality, and several first-in-man-applications as cellular therapeutics have been initiated. The use of hiPSC as the source material for cell-based-therapies helps address the shortage of donor material. While research-grade hiPSC lines are readily available, this is not the case for GMP-compliant hiPSC lines. Implementation of good manufacturing practice (GMP)-compliant protocols for the generation of hiPSC lines is crucial to increase the application safety as well as to fulfil the legal requirements for clinical trials approval.
Producing autologous clinical grade cells for individual patients would pose major logistical difficulties and wide-scale application is likely to be financially prohibitive. A global effort has been initiated to develop donor banks of human leukocyte antigen (HLA)-matched iPSC banks that will serve as an extensive library for selecting close to optimal matches for patients. Because HLA genotypes are highly variable within a population, a bank of several thousand random donors would be required to achieve a clinically beneficial HLA match for a majority of intended recipients; and even with a matching HLA allogeneic cell therapeutics are susceptible to antibody-mediated killing, which subjects the patient to lifelong immunosuppression. GMP-grade iPSCs with reduced immunogenicity have the potential to become off-the-shelf sources for cell-based therapies. Preclinical tests using immunodeficient mice reconstituted with a human immune system (HIS) serve as an important tool to assess the human alloresponse against iPSC-derived cells.
In this project we will screen a large number of immune evasive genes to select the best combination for the generation of an immune evasive iPSC line (Stealth Line), study the immune status of autologous iPSC-derived products in different mouse models and finally, generate a GMP-compliant immune evasive iPSC line that can be used as an intermediate off-the-shelf product for the generation of iPSC-derived clinical products for transplantation in patients.
