Funding opportunities

Develop a cell replacement therapy for Parkinson's disease using human embryonic stem cells

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00688
Principle Investigator: 
Funds requested: 
$55 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Parkinson’s disease (PD) is a devastating movement disorder caused by the death of dopaminergic neurons (a type of neurons in the central nervous system) present in the midbrain. These neurons secrete dopamine (a signaling molecule) and are a critical component of the motor circuit that ensures movements are smooth and coordinated. All current treatments attempt to overcome the loss of these neurons by either replacing the lost dopamine, or modulating other parts of the circuit to balance this loss or attempting to halt or delay the loss of dopaminergic neurons. Cell replacement therapy (e.g. transplantation of dopaminergic neurons into the brain to replace lost cells and restore function) as proposed in this application attempts to use cells as small pumps of dopamine that will be secreted locally and in a regulated way, and will therefore avoid the complications of other modes of treatment. Indeed, cell therapy using fetal tissue-derived cells have shown varying success in multiple transplant studies. Work in the field has been limited however, partially due to the limited availability of cells for transplantation. We believe that human embryonic stem cells (hESCs) may offer a potentially unlimited source of the right kind of cell required for cell replacement therapy. Work in our laboratories and in others has allowed us to develop a process of directing hESC differentiation into dopaminergic neurons. Parallel efforts by clinicians have identified process to implant the cells safely and to follow their behavior in human in a safe non-invasive fashion. Equally important, useful animal models for testing cell therapy have been developed and screening models for discovering novel therapeutic agents have also been established. We therefore believe that the time is right to mount a coordinated team effort such as the one we have proposed to develop a preclinical/clinical platform to treat PD. In this proposal we seek to build a California team with both scientists and clinicians that have the potential to translate a promising idea (a cell therapy for PD) to an investigational new drug (IND) application. Our goals include: 1) Obtaining clinical grade hESCs, 2) Developing a manufacturing protocol to produce the appropriate transplantable dopaminergic neurons in a large scale under the Food and Drug Administration (FDA)-approved conditions; 3) Performing the appropriate safety tests in suitable animal models and to validate tools for noninvasive evaluation (for example by magnetic resonance imaging, MRI) of transplanted cells; and 4) Designing an IRB approved clinical trial protocol so that we can submit an IND application to the FDA. Our proposal of developing hESC-based therapy for a currently non-curable disease (PD) meets CIRM’s primary goal for the Disease Team Initiative and we believe our effort will advance cell-based therapy for PD toward the clinic.
Statement of Benefit to California: 
We have proposed to assemble a team of scientists and clinicians that aim to develop a cell replacement therapy for a currently non-curable disease, Parkinson’s disease, using human embryonic stem cells. We believe that this proposal includes the basic elements that are required for the translation of basic research to clinical research. We have proposed to obtain clinical grade human embryonic stem cells (cells not in contact with animal feeders, serum and proteins), optimize a manufacture protocol to produce the appropriate transplantable dopaminergic neurons in a large scale under the Food and Drug Administration (FDA)-approved conditions; perform efficacy and safety test in suitable animal models and develop tools for noninvasive animal studies (for example by magnetic resonance imaging, MRI) to track transplanted cells; and to design a clinical trial protocol. We believe these efforts not only provide a blueprint for moving Parkinson’s disease towards the clinic for people suffering with the disorder but also a generalized blueprint for the development of stem cell therapy for multiple disorders including motor neuron diseases and spinal cord injury. The tools and reagents that we develop will be made widely available to Californian researchers and we will select California-based companies for commercialization of such therapies. We hope that California-based physicians will be at the forefront of developing this promising avenue of research. We expect that the money expended on this research will benefit the Californian research community and the tools and reagents we develop will help accelerate the research of our colleagues in both California and worldwide.
Review Summary: 
Executive Summary The goal of this proposal is to establish a state-wide team to generate a preclinical and clinical platform for developing cell therapy for Parkinson’s disease (PD). The applicants will derive protocols for the generation of dopaminergic progenitor cells from human embryonic stem cells (hESCs), test these cells in animal models for PD including large animals, develop good manufacturing protocol (GMP) grade cells for human clinical use, and design a clinical trial protocol for patients with PD. Parkinson’s disease is a devastating movement disorder caused by death of dopaminergic neurons. These neurons secrete dopamine and are critical for the function of the motor circuit that coordinates movements in a “smooth” and even fashion. Cell replacement therapy, as proposed in this application, attempts to use dopaminergic progenitor cells derived from hESCs as small pumps that will secrete dopamine locally in a regulated way and therefore avoid the known complications of various other modes of treatment that led to incomplete and failed prior therapeutic attempts. It is firmly established that cell therapy using dopaminergic cell replacement is a realistic strategy. The investigators believe that human embryonic stem cells (hESCs) may offer a potentially unlimited source of the right kind of cell required for cell replacement therapy. Although transplantation will not cure or ameliorate many of the more general symptoms associated with Parkinson’s disease, specific features of the movement disorder will be responsive to the treatment. Together, these factors make Parkinson’s disease an excellent target and one for which there is considerable experimental evidence to support the therapeutic concept. Cell therapy for PD is at a relatively mature stage and there is reasonable expectation for clinical studies within 5 years in this case. Protocols for differentiation of dopaminergic neurons are already established (particularly those based on developmental biology), clinical transplantation in Parkinson’s disease has been studied in the clinic for many years, and there is prior neurosurgical experience transplanting primary cells. For these reasons, Parkinson’s disease represents one of the best avenues to advance stem cell medicine into the clinic. Although relatively young, the Principal Investigator (PI) has shown an impressive ability to gain grant support for stem cell biology and has an excellent publication record in specialist and high profile journals over the last 8 years. The translational expertise of the PI is less clear and s/he has relative little experience building large teams of more senior and qualified individuals. However, s/he has expertise in establishing shared laboratories, a strong point that shows a clear understanding of the need for translational research. Equally, it demonstrates the ability to assume a leadership role in co-ordination and grant writing that will be essential for this project. Moreover, although not yet a leader in the field, the PI has put together a highly experienced multidisciplinary team containing research groups with substantial expertise in hESCs, GMP manufacturing of cells for cell therapy, clinical trial design, and although not totally transparent within the application, groups with experience with animal models of Parkinson’s disease including large animals. Two concerns were raised by reviewers. One of the major hurdles in the proposal is the extent to which the group can actually generate a relatively pure population of dopaminergic neurons for use in clinical therapy. Second, the potential for overgrowth of cells and teratoma formation is not addressed in the proposal, but will need to be discussed in any subsequent submission for the Disease Team Research Award. The applicant has carefully outlined the plans and identification of a multidisciplinary team with expertise in the process of translating a promising idea into a clinical therapeutic application. For each of the proposed steps in the proposal, the PI has identified team leaders and more experienced senior investigators to form part of the proposed team. Impressively, the proposal includes a planned list of deliverables for each of the various phases that they hope to outline as they build the team in this disease team planning award application. In summary, it is very likely that the applicant will be able to prepare a good competitive application in a field that represents and excellent avenue for stem cell medicine that will lead to clinical studies within 5 years, and the review panel enthusiastically recommended this proposal. Reviewer One Comments Concept: Plausibility of this target and evidence in support of this therapeutic concept comes from much prior work in animal models and in humans (particularly those with MPTP-induced Parkinson’s disease), which stresses the likely efficacy of dopaminergic neuron transplantation in Parkinson’s disease. Recent poor results from trials with fetal cells (generating disabling dyskinesias in many patients) underscore the need for highly characterized and validated populations for transplantation. The precise anatomical localization required for the transplantation makes a neurosurgical approach feasible. Although transplantation will not cure or ameliorate many of the more general symptoms associated with Parkinson’s disease, specific features of the movement disorder will be responsive to the treatment. Together, these factors make Parkinson’s disease an excellent target and one for which there is considerable experimental evidence to support the therapeutic concept. There is indeed a reasonable expectation for clinical studies within 5 years in this case, as protocols for differentiation of dopaminergic neurons are already established (particularly those based on developmental biology) and clinical transplantation in Parkinson’s disease has been in the clinic for many years. Given the fact that there is prior neurosurgical experience transplanting primary cells in this disease, it represents one of the best avenues to advance stem cell medicine into the clinic. Principal Investigator: Although relatively inexperienced, the Principal Investigator (PI) has shown an impressive ability to gain grant support for stem cell biology and has an excellent publication record in specialist and high profile journals over the last 8 years. The translational expertise of the PI is less clear, but expertise in establishing shared laboratories shows a clear understanding of the need for translational research. Equally, it demonstrates the ability to assume a leadership role in co-ordination and grant writing that will be essential for this project. Planning Approach: The applicant has logically considered the necessary steps in the planning process and identified individuals at each stage. Furthermore, the team appears appropriately experienced. From my point of view, it is not clear exactly how the planning phase will be used, other than meetings being held, but I believe it very likely that the applicant will be able to prepare a good competitive application in a field that represents and excellent avenue for stem cell medicine. Reviewer Two Comments Concept: Parkinson’s disease is a devastating movement disorder caused by death of dopaminergic neurons. These neurons secrete dopamine and are critical for the motor circuit that coordinates movements in a “smooth” and even fashion. All current treatments attempt to overcome the loss of these neurons by replacing lost dopamine or by modulating other parts of the circuit to balance this loss or attempting to halt or delay the loss of dopaminergic neurons. Therefore, replacement therapy, as proposed in this application, attempts to use these cells as small pumps of dopamine that will secrete locally in a regulated way and therefore avoid complication of various other modes of treatment that led to incomplete and failed prior therapeutic attempts. In fact prior cell therapy using fetal tissue derived cells have shown varying success and helped to establish appropriate surgical transplant studies. In general work in this field is hampered due to the limited availability of cells for transplantation. The investigators believe that human embryonic stem cells (hESCs) may offer potentially unlimited source of the right kind of cell required for cell replacement therapy. In this proposal, they will build a California team of scientists and clinicians that have the potential to translate a promising idea that is cell therapy for Parkinson’s disease to an investigational new drug (IND) application. Their proposal includes 1) obtaining clinical grade human embryonic stem cells, 2) developing a manufacturing protocol to produce the appropriate transplantable dopaminergic neurons in large scale under an FDA approved condition, 3) forming the appropriate safety tests and suitable animal models to validate tools for noninvasive evaluation of cell-based therapy (for example MRI imaging) and, 4) designing an IRB approved clinical trial protocol. Principal Investigator: good Planning Approach: This is a superb proposal from the applicant which carefully outlines the plans and identification of a multidisciplinary team with the expertise in the process of translating a promising idea into an application. The principal investigator (PI) has defined potential team leaders for each of the particular steps including sourcing of good manufacture practice (GMP) grade hESCs, development of a manufacturing process of chemistry, manufacturing , and controls (CMC) of hESC-derived transplantable dopaminergic neurons, testing efficacy and safety in suitable PD animal models, and design of a clinical trial protocol. For each of these steps, the PI has identified more senior investigators with experience in this area to form part of the proposed team. Impressively the proposal includes a planned list of deliverables for each of the various phases that they hoped to outline as they build the team in this disease team planning award application. Overall this is the best organized small disease proposal. The only limitation in this proposal is that the PI has relative little experience building large teams of more senior and qualified individuals. Nevertheless the overall plans are well designed and would be an asset to the future development towards Parkinson’s based cell therapy. Reviewer Three Comments Concept: Cell therapy for Parkinson’s disease is a readily available therapeutic goal. There is proof of concept evidence that transplantation of dopaminergic neurons derived from human fetal tissue can, when enough cells are transplanted, significantly improve clinical symptoms. However, the requirement of a large number of very early gestational age fetuses obtained by elective termination significantly limits this approach. Nevertheless it is firmly established that cell therapy using dopaminergic cell replacement is a realistic strategy. Neurosurgical approaches and patient stratification are still major clinical problems, but assuming that enough dopaminergic progenitor cells can be obtained from human ES cells, this therapy could proceed to human clinical trials within five years. Principal Investigator: The P.I. is a relatively young but highly prolific investigator, and although he has only been running his own lab for three years, he has been highly successful at obtaining research funding and establishing a collaborative research grouping. Although not yet a leader in the field, he has put together a highly experienced multidisciplinary team containing research groups with substantial expertise in hES cells, GMP manufacturing of cells for cell therapy, clinical trial design, and although not totally transparent within the application, groups with experience with animal models of Parkinson’s disease including nonhuman primates. Planning Approach: The approach outlined in this application to use dopaminergic neurons derived from human ES cells is relatively straightforward. It is clear from clinical data that a major determinant for the clinical improvement in Parkinson’s disease patients is dependent on the number of surviving dopaminergic neurons. The PI has outlined a very coherent strategy for taking human ES cell populations into the clinic, but of course the major hurdle in the proposal is the extent to which the group can actually generate A9 dopaminergic neurons for use in clinical therapy.
Conflicts: 

© 2013 California Institute for Regenerative Medicine