Executive Summary This planning award application proposes to put together a team to develop the use of neural stem cell (NSC) transplantation for lysosomal storage diseases (LSDs), which are rare but untreatable childhood diseases resulting from deletions or deficiencies in key enzymatic pathways. In particular Tay Sachs and Sandhoff’s diseases, which are significant clinical targets along with the other LSDs, will be addressed. In this proposal, the applicant proposes to assemble a team to enable a clinical trial using the best stem cells derived from a range of potential sources including: embryonic, fetal or adult brain, bone marrow, reprogrammed cells, amniotic fluid cells and umbilical cells to determine the best candidate for clinical use. In addition, the PI plans to combine this approach with substrate reduction therapy. The concept is that transplanted NSCs may supply the missing enzyme in the diseased brain and also can act through other mechanisms to limit loss of brain function. Reviewers found the proposal not well organized and very confusing. Moreover, the reviewers found a lack of grantsmanship style as the proposal contained large amounts of information in small pictures and small fonts that made the information very difficult to interpret. Reviewers recognized the significance of the target, as Tay Sachs and Sandhoff’s diseases are rare but untreatable and fatal genetic diseases. A major obstacle to current treatment has been the inability to circumvent the blood-brain barrier (BBB) in order to deliver persistent, effective levels of the required therapeutic molecules. NSCs seem to have the correct migratory and developmental properties to address these issues. The evidence for this hypothesis is provided by the principal investigator’s (PI) previously published work and in the preliminary data included in the proposal; however, most of the animal work has been done with central nervous system (CNS)-derived NSCs. A strength of the application is the PI’s persuasive argument that the clinical benefit seen in animal models reflects the combination of enzymatic replacement and neuroprotection mediated by the transplanted cells. Given that the animal model closely resembles the human disease, these diseases represent plausible targets. The proof-of-principle studies have advanced the field to a position where translation and clinical trials are a logical next step, and reviewers felt the concept could enter the clinic within the next five years. However, reviewers discussed several weaknesses which dampened overall enthusiasm for the proposal. The review panel found that the potential risks of transplantation of incompletely differentiated SCs are an essential part of this work and are lacking in this proposal. Moreover, reviewers felt that the proposal lacked adequate consideration of the methodologies to be used to differentiate (or commit) the hESCs prior to transplantation. In this relatively mature clinical concept, reviewers felt that the issues of clinical heterogeneity of the diseases, the ethical issues surrounding transplantation into children, outcome measures for the clinical trials, the likely size of trial required to deliver a clear result and the need for statistical expertise from the earlier stages should have been addressed in the planning approach. Reviewers agreed that the PI is a strength of the proposal. The PI is a well known thought leader and investigator in the NSC field with a strong track record in publications and extensive experience with cellular therapies in models of the LSDs. S/he has led clinical teams and participated in multiple clinical trials and has the appropriate leadership qualities required to lead this program. The planning approach was not well organized. Beyond a symposium and monthly meetings, little detail was given as to how the project would be advanced to the clinic. The application lists a large group of scientists and their expertise as the backdrop to how s/he will carry out the planning process toward a clinical application. The team contains excellent scientists and covers most of the areas required for pre-clinical and translational SC medicine. What is less clear is the expertise in clinical trials. This would need to be considered in the next steps of the planning process. Reviewer One Comments Concept: This planning award application proposes to put together a team to develop the use of NSC transplantation in the lysosomal storage diseases (LSD). These are rare but untreatable genetic diseases resulting from deletions or deficiencies in key enzymatic pathways that in turn result in abnormal accumulation of gangliosides in lysosomes in the CNS and elsewhere. The disease course is characterized by neurodegeneration and inflammation. Plausibility of target The Principal Investigator (PI)has published a number of papers in high impact factor journals showing that NSC transplantation ameliorates the biochemical and clinical manifestations in mouse models of these diseases. He/She has argued persuasively that these clinical benefits reflect combinations of direct enzymatic replacement and neuroprotection mediated by the transplanted cells. Given that the genetic mouse models closely mirror the mutations seen in human disease, these diseases do represent extremely plausible targets and the necessary ‘proof of principle’ experiments have advanced the field to a position where translation and clinical trials are a logical step. Evidence in support of therapeutic concept The principal applicant, both in his/her published work and in the application, provides the necessary preliminary data. A concern would be that the relative contribution of enzymatic replacement and neuroprotection remains somewhat unexplored. However it is important to note that other labs have also provided evidence that such transplantation strategies will be effective in reducing abnormal accumulations in the CNS storage diseases. Can it go to clinic in 5 years? The pre-clinical data certainly provides sufficient evidence that this approach could enter the clinic within a 5 year timescale. What is missing, however, from the proposal, is adequate consideration of the methodologies to be used to differentiate (or commit) the human embryonic stem cells prior to transplantation. Much of the animal work has been done with neural stem cells rather than embryonic stem cells and the potential risks of transplantation of incompletely differentiated stem cells need to be considered. Importance of problem and ability to advance stem cell medicine to the clinic: While these storage diseases are extremely rare, they do represent an ideal avenue for stem cell medicine. They are predictable and (presently) uniformly fatal, and the pre-clinical science is strong. While transplantation into children raises ethical issues of consent etc, from a scientific perspective the plasticity inherent in the developing human brain will be advantageous for transplantation-based strategies. Principal Investigator: Track record of the Principal Investigator (PI) The PI has a strong track record in this area and is undoubtedly one of the most prominent international scientists active in this area. Translational expertise of PI To my knowledge, the PI has not developed these technologies beyond mouse models, and has no expertise in clinical trial design or validation. Leadership qualities of Principal Investigator These are appropriate. Planning Approach: Merit of planning process proposed; is it well thought out? The proposal does not consider sufficiently the issues of clinical heterogeneity, the ethical issues surrounding transplantation into children, outcome measures for the clinical trials, the likely size of trial required to deliver a clear result and the need for statistical expertise from the earlier stages. How good is the team? The team contains excellent scientists and covers most of the areas required for pre-clinical and translational SC medicine. What is less clear to me is the expertise in clinical trials. Consideration of this would need to be an important part of the planning process. Will an award enable the team to prepare a competitive application? Yes, but only if the points above are taken into consideration. Reviewer Two Comments Concept: A multidisciplinary team will pave the way to clinical trials within 3 years. Working groups will focus on addressing the following issues: What source of stem cells (hESC, iPS, etc.) are best to derive the NSC? Clinical scale good manufacturing protocol (GMP) production When, where and how to deliver the NSC? Combination with other therapies (bone marrow transplantation)? What are the best animal models? Patient selection? Repeat treatments? Preliminary data: Figures from Nature paper: In a newborn mouse model, NSC integrate throughout the brain and produce corrective enzyme levels. Similar results in large animals. NSC also seem to inhibit inflammatory responses. NSC treatment may synergize with substrate replacement therapy. Suggest multiple homeostatic action are inherent to NSC fundamental behavior. Treated mice were better than controls, but not cured Reasons for “failure” are not clear, need further basic research. Strengths: The PI Rapid approach to get into the clinic. Significant amounts of pre-clinical data already exist. Mouse, feline, and large animal models Additional funds will be solicited from other corporations and patient advocacy groups. Already spearheading discussions with the FDA regarding the use of NSC for Tay-Sachs Disease. Pre-investigational new drug (IND) meeting scheduled for 3 months. Weaknesses: Research support has only minimal descriptions of the grants. Budget request includes fees to maintain mutant mouse colony, which in my view seems inappropriate for this application. Principal Investigator: The PI is clearly one of the major thought leaders and experts in the field of neuronal stem cells, neurodegenerative diseases, and many other types of brain disorders. He/She is extremely well funded by the NIH, with several grants already focused on the use of NSC for treatment of the diseased brain. He/She is founding Director of the Stem Cell Program at the Burnham Institute for Medical Research, a board-certified pediatrician who has led many clinical teams and participated in multiple clinical trials. The PI holds patents on engraftable NSC, stem cells for cancer, and culture formulations for hESC. S/he is President-elect for the American Society for Neural Therapeutics and Repair. Planning Approach: Planning Approach: 1. Organize symposium on Biology of Children’s Neurogenetic Disorders, with emphasis on metabolic conditions and potential for cell-based therapies. The symposium will serve as the launch point for the planning sessions, attended by team and Scientific Advisory Board (SAB) members. Monthly team meetings, two SAB sessions. Extensive details have been provided in Tables 2 and 3, which contains an impressive listing of SAB/consultants, and working team members that span the entire range of multidisciplinary expertise, industry and academic, needed to rapidly bring this proposal to the clinic. Reviewer Three Comments Concept: The applicant plans to use neural stem cells (NSCs) as therapy in the lysosomal storage disorders (LSDs), in particular in Tay Sachs disease and Sandhoff’s disease, which are significant clinical targets along with the other LSDs. The disease targets are important in that they are incurable, fatal disorders although of low prevalence in the population at large. The concept is that transplanted NSCs may supply the missing enzyme in the diseased brain and also can act through other mechanisms to restore brain function. The evidence for this hypothesis comes most recently from the applicant’s work in a mouse model of Sandhoff’s disease, where transplanted NSCs restored levels of the missing enzyme but also reduced inflammation. In addition, the PI plans to combine this approach with substrate reduction therapy as he has shown that such combined therapy is synergistic. Principal Investigator: The PI is a well known investigator in the neural stem cell field. He/She is currently moderately funded. He/She has a strong track record in publications on NSCs and extensive experience with cellular therapies in models of the LSDs. Through his/her position at the institution where he/she works, the PI is clearly capable of leading such a group that will take these ideas into the clinic. He/She has an extensive network of scientists working in the field. Planning Approach: The PI lists a large group of scientists and their expertise as the backdrop to how he/she will carry out the planning process toward clinical application. The PI believes that the preclinical data achieved to date along with some additional data will lead to at least one clinical trial within three years. To achieve this he/she plans the appropriate IND submission, GMP scale-up of cells etc. The plan is not well organized however and makes for confusing reading. In addition, the applicant should really reconsider his/her grantsmanship style, i.e. not attempt to inlcude huge amounts of information in small pictures and small font. His/her data are good but are spoiled because of the attempts to show everything.