Stem cells have tremendous potential for treating human diseases, as they have the unique capacity to develop into any cell type in the body and to proliferate indefinitely. The development of new therapies based on the transplantation of human stem cells (HuSC) into patients is a major focus of California researchers. A critical step prior to making new HuSC-based therapies available for use in humans is to test their safety and treatment efficacy in research animals that have the relevant disease. The laboratory mouse, widely recognized as the premier mammalian model for studying human disease, is the optimal organism for these preclinical studies. Mice naturally develop many important human diseases, and certain other diseases that afflict humans but normally do not occur in mice can be experimentally induced. While numerous valuable mouse models are currently available, these models must be further developed so that they can accept HuSC transplantation, through suppression of their immune systems. The lack of proven mouse models in which the immune system has been suppressed is a major bottleneck in research to translate discoveries in basic stem cell research to use in the clinic. An additional factor contributing to this bottleneck is a lack of efficient access to mouse models in general. Currently, mouse models are made available from individual laboratories as funds and timelines permit, and, additionally, the mice are generally not bred in quantities or under health conditions suitable for widespread distribution. The recent development at [REDACTED] of immune-deficient mice that support long-term transplantation with HuSCs opens a novel avenue for eliminating the bottleneck of inadequate animal models for preclinical stem-cell studies. At [REDACTED], we will use these immune-deficient strains together with the most valuable existing mouse models of disease to develop a broad array of immune-deficient mouse models of disease. We will also use state-of-the-art facilities to characterize biological traits in these models so that disease progression and the biological response to therapeutic compounds can be accurately assessed. Finally, we will establish and implement mouse production processes for efficient delivery of the desired quantities of mice to California stem cell investigators. It is critically important for CIRM investigators to have the appropriate mouse models to successfully advance therapeutics through the drug development pathway. Overall, this project will significantly accelerate the availability of effective, safe HuSC-based therapies to patients in California and elsewhere.
Stem cells, with their unique capacities to give rise to any cell type and to proliferate indefinitely, have enormous potential for treating human disease. Millions of Californians suffer from the diseases that could be treated effectively through therapies based on transplantation with human stem cells (HuSC). Before HuSC therapies are used in human patients, it is critical to test the safety and efficacy of the therapies using a research animal that has the relevant disease. The laboratory mouse is widely recognized as the most valuable animal model for studying human disease, and reliable mouse models for most of the major human diseases are currently available. However, these models have normal immune systems and are therefore not well suited for testing HuSC therapies, as the immune system recognizes the transplanted stem cells as foreign and attacks them. The lack of mouse models of disease in which the immune system has been suppressed significantly hinders the efforts of investigators in California and elsewhere to develop new HuSC-based disease therapies. An additional impediment is the lack of efficient access to the quantities of mice required for such studies, and to mice whose health, reproducibility, and research effectiveness has been assured. In the proposed project at [REDACTED], we will develop multiple state-of-the-art, immune-deficient mouse models of human disease that can be used for testing HuSC therapies, and we will establish the production processes for making these models readily available to California researchers. This project will benefit Californians by providing broad access to these critical models in the shortest possible timeframe. Further, this project leverages [REDACTED] resident expertise in creating new mouse models and its own investment in state-of-the-art animal production facilities in [REDACTED], allowing California to limit its investment in this type of critical, but costly, infrastructure.
This proposal addresses a bottleneck in stem cell research: access to models of human disease optimized for preclinical testing of human stem cell (HuSC)-based therapies. While there are well-characterized models available for some of the diseases of interest to CIRM grantees, many of these models do not support sustained HuSC engraftment because they have normal immune systems. In Aim 1 the applicant proposes to develop immunodeficient mouse models of type 1 diabetes, Parkinson’s disease (PD), spinal cord injury (SCI), stroke, traumatic brain injury and myocardial infarction (MI), to expand the models that can be used for testing cell therapies. Experimental autoimmune encephalomyelitis (EAE), the most commonly used model of multiple sclerosis (MS), will also be developed in an immune competent background. In Aim 2 the applicant will comprehensively characterize each of the new models, using large-scale studies to optimize protocols, establish therapeutic windows for treatment and validate each model’s utility for disease research. In Aim 3 the applicant proposes to develop scaled-up production and distribution processes for these models.
Reviewers’ opinions about the potential impact of this proposal varied widely. One reviewer felt strongly that the applicant’s approach should be supported; noting that widespread availability of immunodeficient models of disease to investigators would accelerate development of stem cell therapies. However, this reviewer was uncertain whether there is a critical mass of investigators with the facilities and expertise to monitor and study these models but not to produce the models themselves (a market concern). Other reviewers questioned the predictive value of immunodeficient models for some of the proposed diseases. They noted that the natural pathology of many diseases depends on immune function. For example, the development of the desired phenotypes in the models of PD, stroke, MI and SCI may require the presence of inflammatory cells. In these cases, the phenotypes may be more easily achieved by immunosuppression following the induction of disease. Reviewers also questioned the desirability of standardized models for certain diseases. For example, some labs have years of experience generating the EAE model using different protocols than the one proposed by the applicant, and may not want to switch models. One reviewer also noted that a standardized model of MI is currently available for purchase but rarely used. For these reasons, reviewers thought it would have been helpful for the applicant to justify the choice of model of diseases for which multiple models exist.
Reviewers also expressed varied opinions about the feasibility of the research plan. One reviewer cautioned that the proposed models are very sophisticated and it would be a formidable challenge to develop and characterize models for multiple diseases. It was unclear to this reviewer that the necessary expertise was present among the named investigators. In the section of the proposal describing resources, two PhD-level program directors and four PhD-level study directors with expertise in a wide range of diseases are mentioned, but no further detail is provided. The reviewer would have appreciated more information about these collaborators, including biosketches if possible. Without this information, the reviewer was not confident there would be an optimal assessment of pathology in the model systems. However, other reviewers found the research plan both feasible and likely to succeed, and pointed out that the applicant institution has a major track record in producing animal models. They specifically cited the strong preliminary data describing the development of models of stroke, MS, PD and diabetes. One of these reviewers did raise concern about the induction of diabetes using streptozotocin, which provides only a short time window during which animals can be maintained hyperglycemic and suitable for transport to investigators and treatment with cell-based therapies. This timing issue could complicate distribution of the model, but investigators may be able to use insulin therapy prior to treatment with cells.
The reviewers generally found the applicant and research team to be well-qualified to carry out the proposed studies. One reviewer felt the applicant clearly has the experience required to lead the research effort and praised the senior scientist’s strong research track record. However, another reviewer raised concerns about expertise in specific disease models and would have been reassured if collaborations had been established with investigators with specific experience developing and analyzing the various disease models. Reviewers agreed that the applicant’s resources and research environment are outstanding and appreciated the proximity of production facilities to California’s academic and biopharmaceutical research centers, allowing for rapid distribution of the disease models.
Overall, while reviewers appreciated the goal of increasing access to immunodeficient models of disease, they raised significant concerns about the potential impact and feasibility of this proposal.