Element Y (Preclinical Studies)

Element Y: built on an established record of cell transplantation in preclinical models.As described above, our basic stem cell research is focused on fundamentals of human embryonic stem cells, the reprogramming of adult cells to produce patient-specific stem cells, the elucidation of properties of adult stem cells, and the newly-discovered cancer stem cells. Building on a foundation of basic research, the preclinical and clinical disciplines divide classically along lines defined by medical disciplines that emphasize cell function in the context of the whole organism and ultimately the human. Translational biology brings unique demands for supporting technologies and infrastructure. Human tissue acquisition and animal models compatible with human stem cells play particularly important roles in translation. The Lokey Stem Cell (SIM1) design incorporates state-of–the-art resources to support these needs that do not yet exist on the Stanford campus.

Based on our strengths and experience in preclinical science, Stanford University proposed in Part I of this application that initial residents of SIM1, focused on studies in Element Y, will draw from a strong core of scientists and clinical investigators with strengths in: 1) Cancer biology, 2) hematology and immunology, 3) nuclear reprogramming, reproductive and fetal health, 4) neurosciences, 5) endocrinology and diabetes, 6) cardiovascular medicine, 7) musculo-skeletal biology, 8) gastroenterology, and 9) otolaryngology. Reviewers of our Part I grant said: “The institution has an established leadership position in the translation of stem cell biology and preclinical testing. The institution has the breadth to focus on all nine proposed organ systems/disease areas, and is very strong in all areas with a key strength in cancer.” Proof of principle has already been demonstrated in specific diseases, and clear translational potential exists for many projects built on cutting edge ideas.” These strengths also focus the building requirements to support studies in each of these areas. As described in more detail below, the SIM1 design includes facility support for animal model systems and advanced technologies that are essential in each area of research focus.

Stanford has a well-established record of careful and conservative interpretation of cell transplantation in preclinical models, a prerequisite for effective clinical applications that will improve human health. For example, many groups have concluded that stem cells within bone marrow can turn into many different cell types including heart, brain, skeletal muscle, gut, lung, and even sperm and eggs. However, it was at Stanford University that scientists conclusively demonstrated that blood stem cells do not form these cell types and should not be counted on to cure heart disease or neurological disorders. In spite of this demonstration, there are still large ‘stem cell transplant’ trials underway to treat heart disease and neural injury with blood forming (bone marrow) cells. The Core services planned for SIM1 include Stanford’s first fully isolated facility for breeding and maintaining the rare immunodeficient mouse strains that enable this type of research and allow the critical testing of revolutionary concepts in therapy.

Given the ongoing disconnect between careful science and premature clinical treatment, the preclinical research program in Element Y at Stanford University builds on our successes that have been carefully validated in preclinical animal models. One such success is the demonstration in mice that highly enriched human blood stem cells can restore the entire blood and immune system. In such careful, well-validated studies, progress has resulted in successful human blood stem cell transplants in over 70 patients (following FDA and IRB approval at Stanford, Nebraska, Lyon, and MD Anderson). Similarly, several children with a particularly-devastating neural disorder (Batten Disease) that normally results in death within the first decade have been enrolled in clinical trials as approved by the FDA on the basis of similar validation of nervous system stem cells in mice. The SIM1 design recognizes that translation from basic discoveries to animal models and ultimately into the clinic requires close collaboration between scientists and clinicians who are uniquely qualified and uniquely supported with specialized infrastructure. SIM1 incorporates virtually all of these required elements by housing investigators with unparalleled expertise, by providing the supporting services, such as a stem-cell focused GMP facility, and by accommodating access to preclinical and clinical trials support staff.

We are most enthusiastic in planning for SIM1; we believe that our approaches in Element Y are both pioneering and have set the standards for moving discovery to preclinical validation and on to initial clinical trials. Thus, our building plan promotes pre-clinical research through complementary means that include the construction of laboratories conducive to this research and through cores such as the vivarium, rapid autopsy service, tissue bank and imaging to track transplanted cells. Through these new resources (described in more detail in Sections 3G and 4), the SISCB/RM can promote successful pre-clinical studies and advancement of these breakthroughs to clinical stages.

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