New Drug Discovery for ALS using Patient-derived Induced Pluripotent Stem Cells

Funding Type: 
Early Translational II
Grant Number: 
TR2-01832
ICOC Funds Committed: 
$0
Disease Focus: 
Genetic Disorder
Neurological Disorders
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
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.
Progress Report: 
  • 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.
  • For the reporting period, we have obtained primary dermal fibroblasts from clinically affected Canavan disease patients and have derived Canavan disease patient iPSCs. We have demonstrated that these iPSCs exhibited typical human embryonic stem cell (ESC) like morphology, expressed human ESC cell surface markers and hold pluripotency potential. We are also optimizing methods to coax these cells into specific types of neural precursors. Either the patient iPSCs or their neural precursor derivatives will be genetically corrected in the following years to develop a therapeutic tool for Canavan disease patients.
  • 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.
  • 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.
  • For the reporting period, we have demonstrated that the Canavan disease patient iPSCs hold pluripotency potential. We also genetically corrected the patient iPSCs and demonstrated that these genetically-corrected cells maintained human embryonic stem cell-like features. We coaxed these cells into specific types of neural precursors and showed that the genetically-corrected patient cells restored their cellular function. These genetically corrected cells will be tested for their therapeutic effect in the next year, in order to develop a therapeutic tool for Canavan disease patients.
  • 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.
  • 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.
  • We have demonstrated that the Canavan disease patient iPSCs hold pluripotency potential. We also genetically corrected the patient iPSCs and demonstrated that these genetically-corrected cells maintained human embryonic stem cell-like features. We coaxed these cells into specific types of neural precursors and showed that the genetically-corrected patient cells restored their cellular function.
  • For the reporting period, we provided evidence that the genetically-corrected patient iPSC-derived neural precursors were able to produce myelin binding protein in an animal model. We also characterized the Canavan disease mice to show that they exhibited the characteristic Canavan disease patient phenotypes. The genetically corrected cells will be tested in Canavan disease mice for their therapeutic effect in the next funding period, in order to develop a therapeutic tool for Canavan disease patients.
  • 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.

© 2013 California Institute for Regenerative Medicine