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ARRA Investments in Induced Pluripotent Stem Cells (iPS Cells)


Public Health Burden
In late 2007, researchers generated induced pluripotent stem cells (iPS cells) by introducing four genes into human skin cells.  Like embryonic stem cells, iPS cells can both self-renew (multiply) and form specialized cell types.  This groundbreaking discovery allows scientists to produce iPS cells from a patient’s skin cells, and then generate the cell types affected by disease to study cellular mechanisms of disease, screen drugs, and, perhaps, generate cells for therapeutic transplantation.

Improving iPS cell methods and comparing iPS cells to embryonic stemc cells
Researchers must overcome many technical hurdles to realize the potential of iPS cells.  Methods are needed to generate iPS cells efficiently without using viruses to introduce genes, as in the original method for reprogramming skin cells, which might cause cancer or alter the cells’ behavior.  Scientists must also determine whether there are important differences between iPS cells and embryonic stem cells.  Examples of ARRA grants addressing these issues include:
  • Challenge grant scientists are developing a high-pressure jet injection system for rapid, efficient, high-throughput, and reliable delivery of a cocktail of genes or other factors to reprogram cells to form iPS cells without the safety concerns that arise from using viruses.1
  • A GO grant team with several outstanding scientists is comprehensively comparing multiple embryonic stem cell and iPS cell lines and examining the causes, and potential resolution, of any differences.2
Studying disease mechanisms and therapeutic strategies
Research teams are using iPS cells to study many diseases.  For each disease, scientists must generate the appropriate specialized cell types and identify disease specific changes in cells before they can study disease mechanisms and explore potential therapies. Among the many disease-focused ARRA grants:
  • An ARRA Signature project team is reconstructing type 1 diabetes in a mouse using iPS cells derived from human patients. The goal is to identify the cell types and genes responsible for the onset and development of the auto-immune attack on pancreatic beta cells that causes diabetes.3
  • Researchers are creating human iPS cells from patients with hyperlipidemia or common genetic variants of liver drug metabolism and generating hepatocytes (liver cells). This Challenge grant is producing cells that will be useful for investigating liver cell metabolism of lipids and drugs, screening drugs for metabolic diseases, and testing stem cell based gene therapy.4
  • An exploratory grant is studying iPS cells from a child with spinal muscular atrophy (SMA), the leading genetic cause of infantile death, to generate motor neurons, the cells lost in SMA.5
  • Another exploratory grant is using human iPS cells to study the neurobiological defects in Down Syndrome (DS), the most common developmental disorder that leads to mental retardation.6
  • Researchers are generating iPS cells from craniometaphyseal dysplasia (CMD) patients and from control individuals, and comparing formation of osteoblasts (bone forming cells) from these iPS cells in order to identify mechanisms responsible for CMD defect.7
  • GO grant researchers are using iPS cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) to study the mechanisms of the disease and to explore correction of the genetic defect in order to advance cell therapy approaches.8
  • Scientists are deriving iPS cells from people with osteogenesis imperfecta, and using the cells to test a therapeutic strategy for correcting the disease-causing mutation in bone-forming cells. 9
  • A Challenge grant is exploring the use of iPS cells to generate otic cell types as a step toward finding a treatment for hearing loss. 10
  • An exploratory grant is taking a molecular approach to explore the induction of iPS cells into inner ear cells, and discerning the resulting genomic changes through gene chip technology.11
  • A GO grant is generating iPS cells to study the earliest differences in development of cells from individuals with cystic fibrosis or alpha-1-antitrypsin-related emphysema, the two most common inherited lung diseases.12
  • A GO grant is deriving iPS cells in the clinically-relevant porcine cardiac model to generate cardiomyocytes (heart muscle cells) for transplantation to provide preclinical information for future clinical trials of cell therapies.13
  • A GO grant consortium with an exceptional range of experts is developing, characterizing, and studying iPS cell lines for Parkinson’s disease, and will provide cells as a national resource.14
  • A GO grant team is generating iPS cell lines from patients with familial ALS (amyotrophic lateral sclerosis) through a collaborative effort, and studying ALS in cell lines that produce nerve cells and supporting cells that show characteristics of ALS.15
  • A GO grant consortium of researchers is investigating how defective genes lead to Huntington’s disease by studying iPS cells from people with this disease. The consortium will provide validated iPS cells as a resource to the research community.16



  1. 1RC1EB011187-01 -- High throughput cell reprogramming by microfluidic jet injection -- Jensen, K (Contact); Anderson, D; Langer, R (MA)
  2. 1RC2HL102815-01 -- Comparative phenotypic, functional, and molecular analysis of ESC and iPSC -- Daley G (MA, MD)
  3. 3U01DK072473-05S2 -- Beta Cell Biology Consortium ARRA Signature Projects -- Magnuson M; Melton D; Daley G; Grenier D;, Shultz L (MA, NC)
  4. 1RC1DK087377-01 -- Modeling liver metabolism with patient-specific iPS derived hepatocytes -- Duncan, Stephen A (Contact) And Grompe, Markus (WI)
  5. 1R21HD060899-01 -- Motor neuron generation from SMA patient-derived pluripotent stem cells -- Ebert, Allison (WI)
  6. 1R21HD060134-01A1 -- Generation of trisomy 21 induced pluripotent stem cells -- Bhattacharyya, Anita (WI)
  7. 1R21DE019892-01 -- Development of iPS cells to study craniometaphyseal dysplasia in humans -- , Alexander C (CT)
  8. 1RC2AR058919-01 -- FSHD iPS cells: Modeling disease mechanisms, genetic correction and cell therapy -- Kyba, M (MN)
  9. 3R01AR048328-09S1 -- Gene Targeting Strategies For The Treatment Of Osteogenesis Imperfecta -- Russell, David W (WA)
  10. 1RC1DC010706-01 -- Somatic Stem Cells as Vectors to Deliver Biologically Active Molecules to the Inn -- Hashino, Eri (IN)
  11. 1R21DC010042-01 -- Otic progenitors via somatic cell nuclear reprogramming -- Heller, Stefan (CA)
  12. 1RC2HL101535-01 -- Characterization of human hematopoietic and endodermal progenitors derived from -- Kotton, DN (MA)
  13. 1RC2HL101535-01 -- Derivation of Porcine iPS Cells and iPS Cell-Derived Cardiomyocytes -- Longaker Michael T. (CA)
  14. 1RC2NS070276-01 -- PD iPS Cell Line Research Consortium -- Isacson, Ole (MA)
  15. 1RC2NS069395-01 -- Generation and Characterization of Amyotrophic Lateral Sclerosis iPS cells -- Rothstein, JD (Contact); Cudkowicz, ME; Eggan, KC; Henderson, CEdward; Maniatis, TP (MD, MA, NY)
  16. 1RC2NS069422-01 -- Huntington's Disease iPS Consortium -- Thompson, LM (Contact); Finkbeiner, SM; Gusella, JF; Ross, CA; Svendsen, CN (CA, WI, MD, MA)


 
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