Early Translational I
$3 841 240
Recommended if funds allow
Statement of Benefit to California:
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.