A major problem facing stem cell therapy is immune rejection. Immune rejection occurs when the immune system of one person recognizes cells from another person as being “foreign” and rejects them. Foreign cells are recognized because they have a different "HLA-type". Stem cells being studied today are derived from individual persons. These cells are limited in their ability to be used to heal many people other than the individual stem cell donor because of immune rejection. Immune rejection could thus limit the future effectiveness and practicality of stem cell therapy. Immune rejection can be overcome by using drugs, but these drugs are powerful and can lead to bad side-effects.
If HLA-types are similar between two people, then immune rejection is reduced. This fact is the reason why doctors try to match the HLA-types between organ donors and recipients. However, an individual's HLA-type is very unique and complicated because it is composed of a mixture of HLA-types from their mother and their father. This complexity is why it is difficult for doctors to find matching donors with similar HLA-types for their patients in need of an organ or tissue transplant.
Human “parthenogenetic stem cells” (hpSC) have qualities that may allow them to be used in stem cell therapy by large segments of the population with little or no immune rejection. Parthenogenetic stem cells are derived from unfertilized human eggs and thus have no HLA-type contribution from a man. This fact makes the HLA-type of a hpSC much less complicated and easier to match to many people. HLA-matched parthenogenetic stem cells could allow the creation of a bank of HLA-matched hpSC that could be used to treat disease in hundreds of millions of persons with a reduced chance of immune rejection and a reduced need to use immune-suppressing drugs.
Our previous work has resulted in the creation of ten hpSC lines, one line has the most common HLA-haplotype found in the US and can be immune-matched to millions of persons across the world. The hpSC have been shown to have very similar qualities to embryonic stem cells. We have also shown that as with embryonic stem cells, hpSC can change, or “differentiate” into cells that may have therapeutic value.
This research proposal will develop data to prove or disprove the idea that hpSC may avoid immune rejection if they are used for cell therapy in a HLA-matched patient. The research will study the expression of HLA-types in hpSC and will study how immune cells donated by people with matching HLA-types react to these cells in laboratory tests.
Statement of Benefit to California:
This project will benefit California by providing research data to evaluate a unique type of human pluripotent stem cell that may solve the immune rejection problem, one of the most serious barriers to regenerative medicine. These unique stem cells, called human parthenogenetic stem cells, are created from unfertilized human eggs and have a quality that allows immune-matching to millions of persons of differing sexes and racial backgrounds.
Immune matching (or "HLA matching") is used in organ and bone marrow transplants today to reduce immune rejection. If this research shows that immune-matched parthenogenetic stem cells can also reduce or eliminate immune rejection, it would open the door for the establishment of an “immune-matched” stem cell bank. Such a bank of parthenogenetic stem cells with common immune types (called HLA-types) could increase the utility and availability of therapeutic cells and decrease their cost by allowing clinicians to match cells to their patients for many different diseases where stem cell therapy may prove to be beneficial.
A California-based immune-matched parthenogenetic stem cell bank could be a resource used in research and therapeutic applications worldwide in cases where stem cells or their derivatives are studied or needed to cure disease. Intellectual property could be created for California through this resource, resulting in increased valuation for California research organizations and an associated increase in investment, employment and tax revenues.
California scientists are now working intensively with human stem cells because of their great potential to cure many intractable diseases including diabetes, liver disease, retinal disease, Alzheimer’s disease, muscular dystrophy and Parkinson’s disease, to name but a few. Existing parthenogenetic stem cell lines have been shown to produce cell types that may have application in treating several of these diseases. One of these existing lines expresses the most common immune-type found within the U.S. population and thus may have therapeutic utility for millions of Californians. The goal of this research is not only to study the ability of these existing cells to avoid immune rejection, but to create additional parthenogenetic stem cell lines in California under "clinical standards", thus providing a larger database of knowledge as to their potential therapeutic utility and increasing the number of these cells that may eventually be available for clinical use.
Pluripotent stem cell lines can be derived from oocytes by a process called parthenogenesis. The overall aim of this project is to derive human parthenogenetic stem cell (hpSC) lines that are homozygous at human leukocyte antigen (HLA) loci. When compared to unmatched human embryonic stem cells, HLA-homozygous hpSC derivatives may have less likelihood of being rejected if they share a HLA haplotype with the transplant recipient. To test this hypothesis, the applicant proposes to 1) derive four HLA-homozygous hpSC lines from donated oocytes under current good manufacturing practice (cGMP) conditions; 2) collect immune cells from donors that are matched to various numbers and combinations of HLA alleles found on the hpSC lines; 3) use the collected immune cells to assess how the degree of HLA matching affects the in vitro immunogenicity of differentiated cell types derived from HLA-homozygous hpSCs.
Reviewers felt that this project was based on an innovative concept that was poorly developed and lacked scientific rigor. Immune rejection of transplanted cells is a major challenge in moving cell therapy forward into widespread clinical use. However, reviewers commented that the applicant proposes to examine the immunogenicity of hpSC lines in vitro only, and it remains unclear how this can be translated to in vivo transplantation outcomes. Thus, this project would have only minimal impact on the issue of immune tolerance in the near term. Furthermore, the reviewers criticized the fact that the applicant provided no information regarding the HLA haplotypes to be studied, and that in general an in-depth assessment of immunological issues is lacking throughout the application. Reviewers also noted that the applicant did not elaborate how cGMP-compliant derivations would be achieved. Overall, the proposal was considered narrow in scope for a three year funding time frame.
The rationale to pursue HLA-homozygous hpSC derivatives was generally considered appropriate, and reviewers felt that the proposed studies may advance our knowledge on the potential of hpSCs as a source of histocompatible cells. One reviewer commented, however, that natural killer (NK) cells reject stem cell grafts or tissue grafts that do not share all haplotypes with the recipient, and that NK cells that are radio-resistant can reject tissues even in transplants where cells are class I-deficient. Although the applicant proposes assays to study this phenomenon, this raised some concerns about the project’s rationale.
In terms of feasibility, reviewers agreed that the generation of cell lines and the collection of immune cells were straightforward and achievable. The group has shown success in the derivation of hpSC lines, including several HLA-homozygous cell lines. Other aspects of the preliminary results were unsatisfying, however. Although the group claims to have considerable success in the differentiation of hpSC into neuronal, retinal and endodermal cell types, the data presented in the application was overall very descriptive and lacking in specific details. Alternative plans were poorly developed, and no data related to the immunological aspects of the project were presented.
The principal investigator (PI) is the Director for Research and Therapeutic Development at the applicant organization, and will devote 15% effort to the project. The PI is experienced in clinical in vitro fertilization work, although the provided biosketch and publication/patent record indicate limited research experience and insufficient expertise in stem cell biology. In addition, the PI appears to have no previous experience leading research projects of similar size. The designated co-investigator, who will provide the bulk of the immunology expertise, is an Associate Professor at an academic institution and will devote an appropriate amount of time to the project. The PI has assembled a large team of collaborators from a number of different institutions, but reviewers were unclear about the role of most of the individuals and how work at the various sites would be integrated.
Overall, reviewers felt that this project was poorly developed, and would not represent a significant advance in the field of transplant immunology. The research plan was rated as unsatisfying due to concerns with project rationale, limited project scope and limited evidence for achieving meaningful results.