Stem Cell Therapy for the Lysosomal Storage Diseases, the Major Cause of Neurodegeneration in Children
Disease Team Planning
Children with lethal inherited degenerative diseases of the brain, the lysosomal storage diseases or LSDs, should be among the first to benefit from novel approaches based on stem cell therapy (SCT). This belief is based on a number of medical and experimental observations including: 1) These diseases cause profound mental retardation or lead to death in most affected children; 2) SCT has already been shown to work in the milder forms of LSD that do not affect the brain; 3) The safety of neurotherapy for stem cell transplantation is already being established in the LSDs; 4) Many of the pertinent regulatory hurdles have already been overcome; and 5) Experimental work has clearly shown that SCT can be used to treat the brain in the severe forms of LSD. This combination of medical and experimental data strongly suggest that the LSDs are uniquely poised to benefit from novel SCT and that this therapy is likely to be successful, a prediction that can less reliably be made for SCT applied to other brain and spinal cord diseases and injuries. Additionally, results of clinical trials of novel stem cell neurotherapies for the LSDs will be directly pertinent to proposed stem cell neurotherapies for some other neurological diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and stroke, as specific targets for these and other brain and spinal cord diseases and injuries are better identified. Efforts aimed at moving this new SCT into clinical practice, however, will be complex and involve basic, translational, and clinical research as well as the collaboration of multiple clinical centers. As a result, we have already recruited 20 superbly qualified clinicians and translational research scientists to work as a team in moving stem cells into clinical practice to better treat children with LSDs.
Statement of Benefit to California:
Most patients with severe diseases or injuries that might be treatable with stem cells have multiple medical problems and must be seen by multiple specialty physicians. In addition, the translation of experimental stem cell therapies to clinical practice requires the participation of basic and clinical research scientists from a variety of academic backgrounds. Thus, the Disease Team approach to these problems, supported by the California Institute for Regenerative Medicine (CIRM), is an entirely appropriate way to move stem cells from the laboratory to the patient. Our team is focusing on a class of childhood brain diseases that causes the child’s brain to degenerate and results in severe mental retardation or death. These diseases also affect other organs of the body. Many of these organs can already be successfully treated with stem cell therapy. Our team proposes to take these lessons of success and apply them to treating the brain as well. Because of this established stem cell success, this new stem cell therapy, we propose, has a high probability of success. This will not only provide a potential cure for the children that are treated with this new stem cell therapy, but will also benefit California by 1) reducing the State’s burden for caring for these children and 2) providing a successful model of stem cell therapy of the brain that will both bolster public confidence in CIRM’s mission to move stem cell therapies into the clinic, and lay the groundwork for using this type of therapy with other brain diseases such as Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis.
Executive Summary This proposal targets the lysosomal storage diseases (LSDs) through stem cell (SC) therapy. The applicants make the case that enzyme replacement in the central nervous system (CNS) in these diseases has proved difficult and that neural stem cells (NSCs) or mesenchymal stem cells (MSCs) may be good candidates to supply the missing enzyme. The applicant proposes a multimodal treatment strategy, using different SC populations, perhaps in conjunction with other means of enzyme replacement and substrate reduction. Reviewers felt that the problem being addressed in this proposal has great significance as this is a class of diseases that causes end organ destruction, severe mental retardation and/or death in children. While hematopoietic stem cell transplantation can reverse some of the peripheral manifestations of these diseases, the efficacy of reversal of neurogeneration has been limited. The effectiveness of current SC approaches for the treatment of LSDs is limited by insufficient impact on the central nervous system (CNS) and unequal efficacy in all peripheral tissues. This significantly diminishes the quality of current cures. The applicants propose a team that will lead a clinical trial consisting of standard bone marrow SC therapy and enzyme replacement therapy, which would be augmented with combinations of systemic MSC and/or intraventicular MSC or NSC therapies. The reviewers agreed that, while the delivery method, effectiveness and safety of introducing various SC populations are established in a combination of clinical and preclinical studies, the precise SC source for the proposed clinical trial is not yet established. The applicants did not present a plan to determine which SCs should be introduced into the brain, whether differentiation of cells is a necessary component for providing functional enzyme, and whether immune tolerance protocols should be evaluated. If these questions are to be addressed in the context of the trial then a discussion is needed of how the safety and efficacy of testing multiple SC sources would be evaluated with a limited patient population. Reviewers felt that the likelihood of clinical translation within five years is questionable due to many unknowns in this proposal, and considerable pre-clinical work is still needed before a curative strategy can be developed. Reviewers agreed that the PI has good organizational skills and a proven ability to function as a leader of multidisciplinary teams, although the PI is not necessarily a leader in this field. The PI has assembled a large team for the proposed project. Members of the planning team that s/he has recruited bring expertise in the use of hematopoietic cells to treat LSDs, moving MSCs into clinical trials and experience in filing SC-based investigational new drug (IND) applications. While the PI’s background in SCs is strong, his/her experience in leading a translational team is more limited. The proposed plan includes the necessary personnel to execute a clinical trial of augmented SC therapy for LSDs. It also includes a detailed description of how the group will meet and work together to develop a plan, as well as how to address regulatory issues. However, it is not exactly clear how the interactions between the team members will occur. Furthermore, the plan does not provide a description for addressing the unresolved issues around SC sources to treat the CNS or importantly, how they will proceed from animal experiments to a clinical trial in humans. In summary, the reviewers did not find that the plan was sufficiently well developed at this point to recommend it for a Disease Planning Award. Programmatic Discussion: A motion was made to recommend that this application be moved to Tier 3 – Not Recommended for Funding. Concern was expressed regarding the use of a variety of cells in the same therapeutic strategy, although the use of hematopoietic SCs was noted to be a plus. Concern was also expressed for the lack of clarity on how the applicants would transition animal experiments to a clinical trial in 5 years. These concerns were balanced by a consensus that LSDs are probably the best targets for cell therapy and the fact that the existent animal models for LSD are superb. The motion to move this application to Tier 3 failed. Reviewer One Comments Concept: The treatment of lysosomal storage diseases with bone marrow SC transplant is established as effective and safe. However, the effectiveness of current SC approaches is limited by insufficient impact on the central nervous system and unequal efficacy in all peripheral tissues. This significantly diminishes the quality of current cures. In this proposal a clinical trial of standard bone marrow SC therapy and enzyme replacement therapy would be augmented with combinations of systemic mesenchymal SC (MSC) and/or intraventicular mesenchymal or neural SC (NSC) therapies. The target is well established and the therapeutic concept is clear. While the potential SC sources, delivery method, effectiveness and safety are established in a combination of clinical and preclinical studies, the precise SC source for the proposed clinical trial is not yet established. Unknowns include: • Whether peripheral MSC transplantation would be coincident or follow BMT. • Whether MSCs or NSCs would be utilized for intraventricular implantation. • Whether MSCs and NSCs from the same donor or from cell lines would be utilized. • Whether immune tolerance protocols should be evaluated. • What the longevity of transplanted cells will be in the CNS. No experimental plan is described for resolving these issues. It is not clear whether the group feels these should be resolved prior to a clinical trial or be resolved in the context of a clinical trial. If the latter, then a discussion of how limited numbers of patients will impact on the power of a trial to distinguish between the effectiveness and safety of multiple SC sources is required. Therefore it is difficult to judge the maturity of this essential aspect of this study. This is an important clinical problem that has a very high likelihood of advancing the medical applications of SC therapies, and further defining the applications of different SC sources, provided that an appropriate research plan is in place. Principal Investigator: The PI is a recognized leader in human SC science and has a proven ability to function as a leader of multidisciplinary teams. The assembled team provides for the necessary expertise to plan and perform a clinical trial. Planning Approach: The proposed plan includes the necessary personnel to execute a clinical trial of augmented SC therapy for lysosomal storage diseases. The plan includes a detailed description of how the group will meet and work together to develop a plan and a document, as well as address regulatory issues. It does not however provide a plan for addressing the unresolved issues around SC sources to treat the central nervous system. There is no description of an experimental plan to address these issues. There is no discussion of how patient numbers will affect the number of questions that can be answered in a clinical trial setting (whether patient numbers will limit the power to discern differences between different treatment arms). Therefore, I do not believe that the plan is sufficiently well developed at this point. Reviewer Two Comments Concept: This is a proposal to develop SC therapy for lysosomal storage diseases (LSD). The problem is of significance, as this is a class of diseases that causes end organ destruction, severe mental retardation or death in children. While hematopoietic cell transplantation can reverse some of the peripheral manifestations of disease, the efficacy of reversal of neurogeneration has been limited. This team proposes to use SCs to treat the neurodegenerative disease in addition to the other end organs. Bone marrow transplantation is efficacious for preventing much of the peripheral pathology associated with LSDs and clinical trials underway should broaden its application to less severely affected patients. A Phase I clinical trial of human marrow SC injection into the brain parenchyma of some LSD patients is already underway, and will hopefully establish the safety of neurotherapy. MSC transplants have already been shown to be safe in LSD patients and they also have potential therapeutic benefit in tissues where BMT is not effective, such as the bones and joints. MSCs have also been safely injected into the brain of non-human primates. Enzyme replacement therapy in combination with BMT improves the efficacy of BMT, suggesting that these approaches may be synergistic. Intraventricular injection of NSCs has been efficacious in animal models of LSD and pharmacological approaches have improved efficacy. Thus, the clinical and pre-clinical data suggest that this is a mature concept that could soon be applied to patients. The concept of using hematopoietic SCs derived from the same donor as the MSCs and NSCs is a rational approach to overcoming immune barriers that may limit the survival of both NSCs and MSCs. Thus, the rationale is strong. However, there are many unknowns, such as the requirement for differentiation of injected cells in vivo, and it seems that considerable pre-clinical work is still needed before a curative strategy can be developed. Thus, the likelihood of clinical translation within five years is somewhat questionable. Principal Investigator: Dr. Schwartz received his Ph.D. degree at UCLA in 1992. He is a Senior Scientist II at Children’s Hospital of Orange County. He has 46 publications, 10 of which he is listed as senior or first author on. He clearly has strong expertise in generating ES cell lines and has an extensive teaching track record in this area. He has led the hESC Culture Training Course and a National Human Neural SC Resource and has recruited many scientists to participate in SC workshops and symposia. He has assembled a large team for the proposed project. He leads a SC resource that provides cell lines to basic and translational research scientists in a variety of projects. Members of the planning team that he has recruited, including at least 20 faculty, have brought expertise in the use of hematopoietic cells to treat lysosomal storage disease and in moving MSCs into clinical trials. A GMP grade facility at his institution is not described, but the investigator has secured a collaboration with a clinical cell production facility for this purpose. Members of the team are experienced in successfully filing SC-based INDs. Thus, while the PI’s background in SCs is very strong, his experience in leading a translational team is limited. Nevertheless, the strong group of collaborators that he has assembled should help to assure success. Planning Approach: A detailed planning approach, including multiple meetings of translational research scientists, medical geneticists, etc. is described. The development of the document will be performed largely by the PI with input from the team members. The team members listed include individuals with expertise in many different aspects of the treatment of LSDs. However, it is unclear who will conduct the animal research and design strategies to investigate in the animal models. This is an important issue, as the specific strategy to be evaluated clinically has not yet been determined. Reviewer Three Comments Concept: The LSDs while relatively uncommon are nonetheless an attractive target for SC therapy. There is some data in animal models of these diseases that SC therapy can result in normalization of enzyme levels and extend the life of the animal. Autologous mesenchymal cell transplants might be a better source of enzyme than neural SCs in respect to immune rejection of the latter which of course would be allografts. While it might be likely that combined therapies in the LSDs will be required to bring about a cure, the concept here is a long way from clinical translation. Principal Investigator: The PI is a senior scientist at CHOC. He has considerable practical experience with ES cells and neural SCs. He runs a successful ES cell training course, funded by the NIH. His publication record and current grant support is reasonable. He could not be regarded however as a leader in the field although I believe he has considerable organizational skills that are very important here. Planning Approach: The applicant has identified a broad-based group of scientists, both at CHOC and other Californian institutions. However, it is not exactly clear how he sees them interacting. He proposes to hold three meetings whereby the group will take their ideas toward filing an IND. He proposes some state-of-the-art communications to accomplish this, but there is a lack of even an outline of how they will proceed from animal experiments to humans.