Early Translational II
Amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig’s Disease) is a devastating neurodegenerative disorder that leads to progressive muscle weakness, respiratory failure, and ultimately death. It is a relatively common disease, affecting over 25,000 patients in the United States. About 10% of ALS cases are familial (fALS) caused by single-gene mutations, while the remaining 90% exhibit no family history of the disorder and are considered sporadic (sALS). The only treatment available for ALS extends the lives of patients by only a few weeks. This lack of treatment is in part because it has been difficult to design predictive model systems, and also because existing animal models do not represent the heterogeneous disease population. Our goal is to generate a disease model for ALS using patient-derived cells, and use this model to identify new therapies for ALS. Reprogramming patient somatic cells offers tremendous promise for medicine and drug development. Patient-derived induced pluripotent stem cells (iPSCs) can be differentiated into disease-relevant cell types that were previously unavailable, such as motor neurons that reflects the genetic background of that patient with ALS. We propose to generate iPSCs from patients with fALS and sALS, differentiate these cells into motor neurons and glia, and identify in vitro defects in these cells that could reflect the underlying pathology. We will then screen a library of small molecules to identify drugs that reverse this “disease in the dish” model. Finally, we will conduct an in vitro clinical trial to determine whether individual patients might be differentially sensitive to our therapeutic candidate. We believe that this approach, which puts the patients at the forefront of drug discovery, will revolutionize the way we discover drugs for neurologic disorders. If successful, this new drug discovery platform could be applied to a variety of complex diseases where animal and simple cell models are not adequate to address the complexities of the human population. The use of human cells for drug discovery should also shorten the drug development process and increase the rate of success of therapeutic candidates. In addition, the sponsoring institution has fully-integrated iPSC-based drug discovery capabilities, ranging from patient sample acquisition, iPSC line production, cell and molecular biology, high throughput screening and medicinal chemistry. Accordingly, this institution is uniquely positioned to achieve the aims of this grant.
Statement of Benefit to California:
California’s health care system faces significant challenges as millions of children and adults suffer from a host of incurable illnesses. It is expected that health care costs will continue to rise as California’s citizenry ages and requires treatments for age-related, chronic metabolic, cardiovascular, and neurodegenerative disorders. We are proposing to apply iPSC technology to develop therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with no known cures. Based on incidence rate and survival, we and others estimate that there are about 25,000 ALS patients currently in the US. Of these, approximately 2,500 are in California alone. The cost of care for a late-stage ALS patient has been estimated at $200,000 per year, and the overall socioeconomic burden of ALS is very significant. A new therapy could translate to substantial savings to California, in addition to bringing relief to these patients and their families. Our proposed research program will benefit the State of California and its citizens in other ways. First, it will provide a proof-of-principle example for a paradigm shift in drug development for complex neurological disorders. The application of iPSC-based disease modeling and drug discovery to ALS is highly innovative and represents the opportunity to establish worldwide leadership for California in this emerging field. Furthermore, the sponsoring institution will fund approximately 70% of the direct costs during the timeframe of this award. Accordingly, the 3:1 leverage provides great opportunity to magnify the effect of a CIRM award. In addition, iPSC technologies could possibly be extended to drug discovery for other neurological disorders such as Alzheimer’s disease and Parkinson’s disease. Finally, execution of our research program will create new high-paying jobs in the academic, biotechnology and pharmaceutical sectors throughout California. CIRM funding will leverage other sources of investment in this project to help ensure California’s continued future as a world leader in biomedical innovation and translational medicine for the benefit of human health. Lastly, our proposed research program will stimulate California’s economy by creating new enabling tools and technologies that can be broadly adopted across the life science industry, thus promoting development across the academic institutions and biopharmaceutical companies that create biomedical discoveries and advances. These activities will continue to strengthen California’s leadership position at the forefront of the stem cell and regenerative medical revolution of the 21st century.
The applicants are seeking a Development Candidate Feasibility Award to generate induced pluripotent stem cell (iPSC) lines from patients with familial and sporadic amyotrophic lateral sclerosis (ALS) to identify possible in vitro phenotypes that might be related to the underlying pathology of the disease. The applicants anticipate that they will succeed in identifying a phenotype that can then be used to screen a library of compounds and identify candidate compounds that would reverse the phenotype. Candidate compounds would be subjected to optimization and testing in a panel of diverse patient lines to evaluate effectiveness across a broad patient cohort. Reviewers agreed that finding molecules that might reverse or cure ALS, a devastating and costly disease, could have a potentially high impact. They recognized the significance of addressing ALS through iPSC technology, since an approach based on patient cell-derived motor neurons and glia enables identification of target phenotypes that are physiologically relevant. All discovery work in recent years has utilized fibroblasts and engineered cells that lack the human ALS genotype and phenotype. This is particularly important since multiple genes that may be common to both familial and sporadic ALS are involved. A phenotypic approach may lead to an assay that targets one or more of these genetic defects or aberrant pathways. However, it was also noted that ALS pathology involves three different cell types and effects on motor neurons can be both cell-autonomous and non-cell-autonomous, which will make the development of an in vitro assay quite challenging. The reviewers appreciated certain aspects of this study including access to patient-derived dermal fibroblasts, expertise in iPSC differentiation to motor neurons, and availability of a well-characterized compound library for screening. However, a crucial weakness is the lack of a well-defined ALS phenotype in the iPSC-derived motor neurons. Hence, the criteria to identify active compounds that reverse ALS phenotypes in the high throughput screen cannot be determined. Reviewers emphasized that developing a meaningful phenotypic assay is very challenging, especially because three different cell types may contribute to ALS disease etiology. The work plan assumes that the scientists will, by the start of any CIRM funding, have identified a biochemical and/or morphological measure of neurodegeneration that can be used as a screen. Various options such as stressing cells are discussed by the applicants. However, in the absence of an in vitro phenotype, reviewers expressed serious doubts that the objectives of this study can be achieved. Additionally, reviewers found that the work plan for assay development was not fully convincing. For example, it was noted that validation data for the optimized assay conditions, such as plate uniformity or motor neuron lot differences, were not provided. These were thought to be important parameters for evaluating the proposed screen. Reviewers felt that the principal investigator and research team are very strong and experienced in generating iPSCs and motor neurons for screening, and appreciated that the team includes expertise in neurobiology, medicinal chemistry and high throughput screening with drug discovery and development experience. The environment and resources to conduct the project were well regarded and reviewers noted strong collaborations with ALS experts and appropriate support letters. In summary, despite an excellent research team and resources to conduct the proposed project, reviewers thought that the lack of a well-defined in vitro phenotype and the lack of a good plan to develop an assay made the project unfeasible in the time proposed.