Early Translational II
Canavan disease is a devastating disease of infants which affects their neural development and leads to mental retardation and early death. It occurs in 1 in 6,400 persons in the U.S. and there is no treatment so far. We propose to generate genetically-repaired and patient-specific stem cells (called iPSCs) from patients’ skin cells, and then coax these stem cells into specific types of corrective neural precursors using methods established in our laboratories in order to develop a therapeutic candidate for this disease. By use of a mouse model of Canavan disease, we will determine the ability of these genetically corrected cells to successfully treat the disease. These results will form the basis for an eventual clinical trial in humans, and if successful, would be the first treatment for this terrible disease. There are many families affected by this disease, and other diseases similar to it. Results from this work could have applications to this and other similar genetic diseases. Through the proposed research, maybe no parents will have to watch their child suffer and die as a result of these dreadful diseases in one day. What a wonderful day that would be!
Statement of Benefit to California:
It is estimated that California has ~12% of all cases of Canavan disease in the U.S. Besides the tremendous emotional and physical pain that this disease inflicts on families, it produces in California a medical and fiscal burden that is larger than any other states. Thus, there is a real need to develop a strategy of treatment for this disease. Stem cells provide great hope for the treatment of a variety of human diseases that affect the citizens of California. Combination of gene therapy and iPSC technology will enable the development of therapeutic candidates of human genetic diseases via the creation of genetically-corrected patient-specific iPSCs. Our proposal aims to establish a therapeutic development candidate for Canavan disease, a devastating neurodegenerative disease that leads to mental retardation and early death. The generation of genetically-repaired and patient-specific iPSC lines will represent great potential not only for California health care patients but also for pharmaceutical and biotechnology industries in California. Moreover, California is a strong leader in pre-clinical and clinical research developments. To maintain this position, we need to create patient-specific stem cells as autologous therapeutic candidates, in order to overcome the challenges of immune rejection faced by today’s cell therapy field. This proposal addresses the very issue by generating “disease-corrected” and patient-specific iPSCs as a therapeutic candidate with the potential to create safer and more effective cell replacement therapies.
The objective of this Development Candidate Feasibility Award application is to establish a development candidate for Canavan disease (CD), a rare but devastating neurodegenerative disease for which there is currently no effective therapy. CD is caused by gene mutations in the aspartoacylase (ASPA) gene. The therapeutic strategy is to restore ASPA enzyme activity by combining patient-specific, induced pluripotent stem cells (iPSCs) with gene therapy to develop genetically corrected patient iPSCs. These iPSCs will then be differentiated into neural precursors to provide a cell replacement candidate to alleviate the disease phenotypes of CD. The Specific Aims are: 1. To generate genetically corrected iPSCs (ASPA iPSCs) from Canavan disease patients’ fibroblasts; 2. To use these ASPA iPSCs to derive neural progenitor cells (NPCs) or oligodendrocyte progenitors (OPs), both of which have been shown to reach regions of tissue damage and differentiate into myelinating oligodendrocytes in the brain; and 3. To test the therapeutic effect of the ASPA iPSC-derived neural precursors in a CD small animal model. This study may lead towards a therapeutic candidate for CD. Reviewers agreed that the target for this proposal is sound. There is substantial knowledge regarding the etiopathogenesis of CD and the rationale for cellular replacement with NP (or OP) cells capable of producing the missing enzyme is strong. This approach should result in amelioration of the disease, assuming integration and persistence of the cells. One reviewer pointed out that there are published data showing that genetic introduction of the ASPA gene into the striatum of the CD mouse increased local levels of enzyme and improved spongiform pathology near the injection sites. Reviewers agreed that if successful, this project would have a major impact on CD patients. Moreover, despite CD being a rare disease, the success of this project would serve as a good model for other diseases. Reviewers viewed the feasibility of the research plan as straightforward, reasonable and achievable. The aims are focused and achievable within 3 years. Reviewers did suggest that Aim 1 would have benefited from transient reprogramming with transcription factors rather than permanent integration. Reviewers agreed that Aim 2 is a key strength of the proposal, although one reviewer recommended that the applicants also consider the loss of ASPA in astrocytes (besides oligodendrocytes) as the cause of the disease. Regarding Aim 3, reviewers expressed a concern that the human iPSC-derived neural precursors will generate an immune response in the mouse model of CD and commented that this was not discussed. The principal investigator (PI) is a well-trained researcher who has contributed significantly to the field of neural stem cells. Reviewers were extremely enthusiastic regarding the collaboration between the PI and the collaborative funding partner (CFP) PI, describing it as very strong. However, one reviewer commented that the percent effort that the CFP PI will dedicate to the project (10%) is on the lower side of what may be optimal for this project. Reviewers agreed that institutional support is excellent. Facilities for both institutions were also found to be excellent. Together with the availability of both Canavan disease mice and vectors to correct the genetic defects, all the facilities and collaborations necessary for this project are in place. Overall, this is a solid DCF proposal for the neurodegenerative disorder, Canavan disease. Strengths for the proposal include excellent therapeutic and scientific, a straightforward and achievable research plan, and an accomplished research team with appropriate expertise. Although reviewers had minor concerns about the project’s feasibility, they recommended it for funding.