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RL1-00638-1: Human Germ-Line Stem Cells As Source for Pluripotent Stem Cells

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

We seek to extend our current findings obtained with laboratory mice to human patients. In particular, during the course of the proposed research, we aim to develop routine protocols for isolating and amplifying autologous Germ Line Stem Cells (GLSC’s) from patient-biopsy specimens that retain their potency and are subject to minimal manipulation under sterile technique (amenable to regulation according to cGMP [current Good Manufacturing Practice]). In the future, we expect to translate this technology into clinical application for individualized treatment of male juvenile cancer patients undergoing radiation- and/or chemotherapy-induced treatments that result in infertility, where the freezing of sperm for future use is not yet an available option. Finally, we believe these techniques can be extended to female oocytes as well, where they will play a similar role in treating female infertility as well. Ultimately, these cells, because of their pristine nature compared with other types of stem cells, can be used to treat a wide variety of chronic diseases.

Statement of Benefit to California (provided by applicant)

Basic research into the biology of mammalian adult stem cells based on experimental animals, such as laboratory rodents, is expected to benefit the citizens of California by establishing rigorous protocols for Phase-I human clinical trials in the future for a wide range of chronic diseases from neurodegenerative disorders (Parkinson’s, Alzheimer’s), heart disease, stroke, lung diseases (COPD), Diabetes, traumatic injuries (spinal-cord and head trauma from sports injuries or car accidents), congenital genetic disorders (Huntington’s, Sickle Cell Anemia), post-radiation cancer treatments leading to infertility, and many others. The reason for working with laboratory animal-models of human disease is to establish clinical guidelines for treatment that are not well understood at this time. Some of the clinical procedures that have yet to be resolved are the following: • rigorous characterization and standardization of cultured human stem cells prior to administration; • purity of the cells, e.g., without contamination by mouse feeder cells or oncogenic viruses; • individualizing of doses of cells per administration (from thousands to possibly millions of cells); • frequency of administration (daily, weekly, monthly, annually, or possibly only once); • route of administration (IV perfusion vs. organ-specific injection); • degree of differentiation of the cells (full pluripotent vs. multipotent or organ-specific cells); • the absolute requirement for autologous cells (to prevent acute rejection and/or graft vs. host disease) vs. the sufficiency of non-histocompatible cells, as claimed by some respected scientists; • diagnosis of end points for the successful termination of treatment; • prognosis of systemic side effects or adverse reactions (inflammation, autoimmune disorders, cancer). It is essential for citizens of California that the first human clinical trials conducted in our state be subject to the most rigorous protocol information available before such trials could lead to potentially serious adverse reactions, as we have witnessed with the otherwise promising field of genetic engineering and in the case of at least one profit-making, off-shore clinic where desperate patients, lacking alternatives, suffered the adverse consequences of tissue rejection from incompatible human fetal-cell injections. We are confident that CIRM-funded animal stem-cell research will provide the rigorous foundation for California medical scientists to build the protocols that will be needed for human therapies in the not-too-distant future.

Review

This proposal aims to derive new pluripotent cell lines from male germ cells that could be utilized for treatment of male infertility, for fundamental biology studies of male germ cells, or as a tool for drug screening. The applicants propose to initiate studies with an animal model and ultimately to derive human cells under good manufacturing practice (GMP) conditions.

Reviewers felt that the significance of exploring and developing a new source for pluripotent cells is great. However, the research plan to achieve this was poorly formulated. Experimental approaches were lacking in critical areas that made it difficult for the reviewers to assess whether meaningful data would be generated. Of particular concern was the fact that the proposed studies have to date only been accomplished in mice and it is unclear if the proposed strategy will translate to larger animal models and humans. This is an important consideration given that culture conditions for mouse and human cells are very different. If the approach does not translate, then the project fails. The applicant will recruit the assistance of several collaborators who are critical in the acquisition of tissue samples and cell sorting facilities.

Reviewers indicated that no plans for distribution of the derived cells were presented by the applicant.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None