Engineering Universal Donor Stem Cells

Universal Donor Cells

Human pluripotent stem cells (PSCs) have the potential to treat diseases affecting almost every organ system.  Hematopoietic cells derived from PSCs are especially promising, given that methods for their transplantation and transfusion are well-established, and they need not form anatomically complex organs. However, the clinical use of PSC-derived products is limited by allogeneic rejection, primarily due to differences in the diverse human leukocyte antigen (HLA) genes, and the use of autologous induced PSCs or the establishment of HLA-typed PSC banks are problematic due to the large number of cGMP-grade cell lines that must be prepared. Here I will describe an approach for generating universal donor PSCs, which will allow a single PSC-derived cell product to be used in multiple allogeneic recipients.  Gene editing with recombinant adeno-associated virus vectors is used to efficiently alter genes involved in HLA expression, without the use of potentially genotoxic nucleases. Through this process, we eliminate cell surface expression of both HLA class I and class II molecules, which prevents peptide presentation to T cells. An additional gene editing step is used to reintroduce a non-polymorphic class I molecule and thereby prevent lysis by Natural Killer cells. HLA-engineered PSCs can be differentiated into therapeutic cell products that are compatible with all recipients.