GABAergic Interneuron Progenitors Derived from Isogenic, ApoE-Corrected Human Induced Pluripotent Stem Cells (iPSCs) for Treatment of ApoE4-Positive Alzheimer's Disease (AD)
Early Translational IV
$6 417 954
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting over 480,000 individuals in California alone—more than in any other US state—and over 5.4 million individuals in the United States. AD causes the loss of brain cells, or neurons, in brain regions controlling learning and memory. The mechanisms that cause AD are complex, with multiple individual genes and proteins involved. One of these is apoE—a protein essential for the health and repair of neurons. In humans, there are three forms of apoE (apoE2, apoE3, apoE4), and one, apoE4, is the single biggest genetic risk factor for AD. Because of its complexity, AD presents unique challenges for developing traditional therapies. Induced pluripotent stem cells (iPSCs) generated from skin cells provide a way to replace the neurons that are lost in AD, and pave a new path towards effective therapies. However, current iPSC-based therapeutic approaches for AD do not consider apoE4's impact, which could lead to clinical failure. We found that apoE4 causes the loss of a selective subpopulation of neurons in the region of the brain important for learning and memory, and that loss of these neurons correlates with the severity of learning and memory deficits in mice. We propose to develop and optimize conditions to generate these lost neurons in a culture dish using iPSCs from AD patients for transplantation studies. Importantly, we will correct patient iPSCs that carry apoE4 to the protective apoE3 or apoE2 form.
Statement of Benefit to California:
Alzheimer's disease (AD) is the leading cause of dementia and is the fastest growing form of cognitive impairment in California. Currently, there are over 480,000 AD patients in California—more than in any other US state—costing over $20 billion USD in healthcare and lost productivity in 2012 alone. This research project focuses on developing patient-specific cell-replacement therapies for AD. We will generate multiple human induced pluripotent stem cell (iPSC) lines in which the AD-causing apoE4 gene is corrected to the protective apoE3 or apoE2 form. Successful completion of this research could foster the development of new technologies that could contribute to the California biotechnology industry. For example, these cell lines could be valuable for biotechnology companies and researchers who are screening for drugs targeting AD. Furthermore, the knowledge that will be gained through the proposed studies should also be helpful for biomedical researchers to develop beneficial therapies beyond what is currently available. As many neurodegenerative diseases share pathological features with AD, including subtype-specific neuron loss, this project could also provide proof-of-principle that cell replacement is an effective approach for treating other neurodegenerative disorders that burden Californians. Finally, this research could help to improve the health of Californians and reduce the adverse impact of AD, thereby increasing productivity and enhancing quality of life.
This is a Development Candidate (DC) application that proposes to develop a patient-specific cell-replacement therapy to treat apoE4-positive Alzheimer’s disease (AD). The proposed DC is autologous patient induced pluripotent stem cell (iPSC) derived GABAergic interneuron progenitors genetically corrected to express a protective APOE gene. The work has two main objectives. One objective is to demonstrate the safety and efficacy of these cells for restoring normal learning and memory in two AD mouse models following transplantation of these cells into an area of the brain critical for memory. The second objective is to develop a robust manufacturing protocol to derive and expand the proposed DC from iPSC. Objective and Milestones - Reviewers questioned whether the proposed target product profile was scientifically and clinically reasonable given the disease indication and given the proposed patient-specific genetically corrected differentiated cell therapy candidate. - Reviewers considered the milestones to be well organized but encouraged more thought on success criteria. Rationale and Significance - AD is the number one neurological condition for ageing populations in the western world, and the proposal therefore addresses a major unmet clinical need. - AD pathology affects broad regions of the brain, well beyond the targeted region of the brain proposed for therapy. Furthermore, apoE4, while a risk factor, is not by itself causative for the disease. Therefore, the proposed APOE4 gene correction and focal cell replacement strategy is not likely to succeed in AD patients. - Reviewers doubted that such a complex DC (patient-specific, genetically corrected iPSC-derived interneuron progenitors) would ever be a frontline treatment for AD. Feasibility and Design - This proposal builds on the applicants' findings from recent studies in AD mouse models. While the preliminary data using homologous cells in AD mouse models was strong, reviewers did not find the data supporting the proposed ApoE4 mechanism in human iPSC-neurons convincing. - The panel was unconvinced that the applicant could get human cell engraftment in immune competent mouse models as proposed. They cautioned that finding an effective immunosuppression regimen and demonstrating engraftment would be challenging. - Reviewers felt the proposed transplant control was highly inappropriate and likely to lead to a false positive conclusion regarding the efficacy of the DC. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI has extensive experience in the area of AD pathology, molecular biology and mouse models. The Co-PI brings further stem cell expertise. Collaborations, Assets, Resources and Environment - The collaborators are excellent but reviewers questioned the very low percentage commitment of some of the collaborators and considered it inadequate to impact the program’s progress. - The host institution is considered an excellent place to carry out the work proposed. Responsiveness to the RFA - Reviewers did have any relevant concerns under this review criterion.