Martin Pera stem cells and the future of medicine

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Martin Pera stem cells and the future of medicine

  1. 1. Stem Cells and the Future of Medicine<br />Martin Pera<br />Eli and Edythe Broad<br />Center for Regenerative Medicine<br />And Stem Cell Research at USC<br />
  2. 2. What is regenerative medicine?<br />An emerging field of therapeutics that has as <br />its goal the restoration of normal function in <br />conditions characterised by cell loss, caused by <br />disease or injury. <br />Restoration may involve the administration of cells <br />to replace damaged tissue, alone or in combination <br />with synthetic scaffolds, or the administration of <br />pharmaceuticals that help drive the patient’s tissue<br /> to repair itself.<br />
  3. 3. What is a stem cell?<br />A primitive cell with two key properties:<br />Self renewal, or the ability to divide many times to produce more stem cells<br />The ability to undergo differentiation or specialisation to give rise to mature functional cells<br />Stem cells have the potential to replace dead or damaged cells in diseased tissue<br />
  4. 4. Tissue Stem Cells<br />
  5. 5. Clinical uses of tissue stem cells<br />Bone marrow and cord blood-hematopoietic disorders, leukemias<br />Mesenchymal stem cells-cartilage repair<br />Neural stem cells-early phase trials <br />
  6. 6. Limitations with tissue stem cells<br />Rare-minority population in most tissues ie less that 1/1000<br />Usually have a limited repertoire-can only give rise to a few types of differentiated cell<br />Not well characterised in many tissues<br />Difficult to propagate and expand in numbers outside of the body<br />
  7. 7. Nov 98- human embryonic stem cells discovered<br />
  8. 8. Human embryonic stem cells<br />Derived from spare embryos before specialised tissue of the body begin to form<br />Can multiply indefinitely in laboratory cultures<br />Retain the ability of embryonic cells to turn into any type of tissue<br />
  9. 9. Early stages of human development<br />
  10. 10.
  11. 11. hESC differentiation<br />Teratoma formed by human ES cells shows<br /> differentiation into a wide variety of cell types<br />
  12. 12. ES cell differentiation follows the road mapof embryogenesis<br />
  13. 13. Partial list of cell types derived from human ES cells in vitro<br />Nerve, astrocyte, oligodendrocyte<br />Hematopoietic stem cells<br />Insulin producing cells<br />Cardiomyocytes<br />Hepatocytes<br />Endothelial cells<br />Bone forming cells<br />Motor neurons<br />Trophoblast and yolk sac cells<br />
  14. 14. Somatic cell nuclear transfer and reprogramming<br />Many species of mammal have now been cloned.<br />Can cloning technology be used to surmount immunological<br />barriers to stem cell transplantation? <br />
  15. 15. Somatic cell nuclear transfer<br />
  16. 16. Induced pluripotent stem cellsMatching cells for patients<br />Skin cells taken from adult tissue are grown in a dish<br />2-4 genes found in embryonic stem cells are introduced<br />Adult cells are converted to pluripotent stem cells<br />These stem cells provide a match for the patient<br />
  17. 17. Induced Pluripotent Stem Cells: The potential<br />Creation of large banks of stem cell lines of desired HLA haplotypes for tissue matching<br />Development of in vitro models of diseases with complex genetic susceptibility<br />Partial reprogramming to heal tissues: exocrine pancreas to endocrine pancreas<br />
  18. 18. Induced Pluripotent Stem Cells: Challenges<br />Can we make these cells without genetic modification?<br />Are they really equivalent to human embryonic stem cells<br />Embryonic stem cell research is still needed as is research in somatic cell nuclear transfer<br />
  19. 19. Stem cell research will revolutionise medicine<br />Powerful new tools to study human biology in health and disease<br />Normal human cells to study in the laboratory-use to develop new drugs. Alternative to animal models or direct tests on human guinea pigs.<br />Cells for replacement therapy in devastating conditions involving cell loss or injury<br />New understand of how the body’s natural healing process, how and why it fails, and how to improve healing<br />
  20. 20. Stem Cells to Study Disease<br />Marchetto et al. Cell Stem Cell 3: 649, 2008<br />Amyelotrophic lateral sclerosis<br />
  21. 21. Stem Cells to Study CNS Development<br />Cortical structures in vitro from human ES cells<br />Eiraku et al. Cell Stem Cell 3: 519, 2008<br />
  22. 22. The Eli and Edythe Broad CenterFor Regenerative Medicine and Stem Cell Research<br />
  23. 23. Broad CIRM Center Opening29 October 2010<br />
  24. 24. The Center<br />Established April 2006<br />Built on strengths in developmental biology, clinical research, stem cell biology at Keck School and CHLA<br />$50 million dollar commitment by USC to program development<br />Now 12 PIs, over 100 staff, four core laboratories. Four administrative staff<br />
  25. 25. Center Research StrategyDiscovery Technology Treatment<br />Patient treatment<br />And clinical trials<br />Platform technologies:<br />Large scale production<br />Drug discovery, functional<br />genomics<br />KSOM clinical <br />groups<br />Engineering, Biotech,<br />pharma<br />Basic discoveries <br />in stem cell biology<br />
  26. 26. Center Discovery Research ThemesStem Cell Biology<br />Embryonic stem cell growth and differentiation; reprogramming adult cells <br />Biology of tissue regeneration and repair; how stem cells are controlled in the body<br />How cells are shaped to form organs<br />
  27. 27. Embryonic stem cells from rat<br />Chimeric rat pups made<br />from embryonic stem<br />cells. Chimeras are black<br />and white. <br />
  28. 28. An important new tool for basic research and drug discovery<br />Workers have tried for 20 years to make rat embryonic stem cells<br />Rats are widely used in physiology and pharmacology and drug discovery<br />Until now there have been no tools to make specific modifications in the rat genome to create disease models, like we can in mouse (Nobel prize 2007)<br />Ying used his new discoveries about embryonic stem cell growth regulation (ES cell self renewal as a default pathway) to make rat ES cells for the first time<br />
  29. 29. Science Magazine Top Ten Breakthroughs of 2010<br />Gene knockout rat technology developed by Dr. Qilong Ying<br />named one of Top Ten Breakthroughs of 2010 by <br />Science magazine<br />
  30. 30. Understanding tissue repair and regeneration<br />Lower vertebrates can <br />regenerate limbs, hearts and <br />kidneys.<br />How does this work?<br />What stops this happening<br />in mammals?<br />How do tissue stem cells function<br />in repair?<br />
  31. 31. Skeletal regeneration<br />In Mammals<br />Dr. Francesca Mariani<br />
  32. 32. Stem Cell Transplantation Biology<br />Dr. Gregor Adams and colleagues have identified a <br />drug that promotes engraftment of <br />blood stem cells in transplant recipients.<br />The findings may lead to more effective treatment of blood <br />disorders and cancers.<br />
  33. 33. Blindness<br />Macular degeneration is a major cause of blindness in the aging population<br />
  34. 34. Retinal pigment epithelium and macular degeneration, a major cause of blindness<br />
  35. 35. 2000- hESC can form neural tissue in vitro. The eye forms<br />as an outgrowth of the embryonic brain<br />
  36. 36. 2004-directed neural <br />differentiation<br />Treatment with the embryonic head inducer noggin<br />induces differentiation of human ES cells into primitive neural tissue<br />Nestin and Sox-2, markers of early neurogenesis<br />Groppe et al. Nature<br />420: 636, 2002<br />Conservation of developmental mechanisms<br />
  37. 37. Retinal pigment epithelium from human neural progenitors<br />Doheny Eye Institute and Center Collaboration<br />
  38. 38. The road to the clinic:<br />ES cells for eye disease<br />
  39. 39. CIRM Macular Degeneration Disease Team:The California Project to Cure Blindness<br />USC Doheny Eye Institute (Mark Humayun, PI; David Hinton Co-PI; Vas Sadda, Biju Thomas, Martin Pera)<br />UCSB Macular Degeneration and Stem Cell Centers (Dennis Clegg, Co-PI; Lincoln Johnson)<br />UCL London Project to Cure Blindness (Pete Coffey, Partner PI funded by MRC)<br />Caltech Biology and Chemistry (Scott Fraser, Bob Grubbs, Yu-Chong Tai)<br />City of Hope Center for Biomedicine and Genetics GMP Facility (Larry Couture)<br />
  40. 40. Chemical genomics and stem cells<br />Stem cells can be used in high throughput screens to discover new small molecules that modulate tissue regeneration or repair<br />Important tool to understand stem cell control pathways-but also leads for drug development<br />
  41. 41. Dr. Kahn has focused on WNT signaling, a key pathway in development and cancer<br />The Wingless mutation affects wing development in the fruit fly embryo.<br />The Wnt gene, discovered as a virus integration site for mouse breast cancer induction, is involved in many cancers.<br />Like many developmental pathways, Wnt is evolutionarily conserved and widely deployed in stem cell regulation in many tissues. <br />
  42. 42. USC Center for Molecular Pathways and Drug Discovery<br />A joint venture between the Broad Center at USC and the USC Norris Cancer Center<br />Directed by Professor Michael Kahn (Broad) and Professor Heinz Lenz (Norris Cancer Center)<br />Mission: discover new chemicals that modulate critical signaling pathways in stem cells and cancer and develop new therapeutics<br />
  43. 43. CBP/Catenin Antagonists Effectively Eliminate Cancer Stem Cells<br /> When Used in Combination Chemotherapy<br />Mice are cancer<br />free<br />
  44. 44. Cancer Therapy Program at NCI Considers the Development of PRI-724 its Highest Priority“PRI-724 is a first in class and first in human agent. PRI-724 is a novel cancer stem cell targeting agent…” There are no other Wnt signaling pathway inhibitors targeting transcription.<br />Phase I clinical trial 7 day continuous infusion of C82 (primary endpoint MTD/biological activity, secondary endpoint proof of principle Survivin expression in tumor and CTC)-later this year<br />No toxicity to normal tissues indogs at 200X IC50 (the dose that kills 50% of tumor cells)Ph<br />
  45. 45. Zinc finger nuclease-based stem cell therapy for AIDS<br />- $14 million CIRM Disease Team award<br />City of Hope AIDS lymphoma group<br />Paula CannonAssociate Professor, Microbiology & Immunology<br />USC Keck School of Medicine<br />Dave DiGiusto John Rossi John Zaia<br /> (PI)<br />
  46. 46. The AIDS virus must enter cells to infect them.<br />HIV-1 enters cells by binding to CD4 and a co-receptor, CCR5<br />CD4 and CCR5 are proteins on the surface of <br />cells that the HIV-1 targets.<br /><ul><li>About 1% of people have 2 copies of a mutant version of CCR5 gene called CCR5D32, and theyare consequently extremely resistant to HIV-1.
  47. 47. The virus cannot enter their cells.</li></li></ul><li>Can we make AIDS resistant cells byblocking CCR5 expression in hematopoietic stem cells and their progeny?<br />HIV<br />CLP<br />T cells<br />B cells<br />ProB<br />Bone marrow stem cells<br />are the source of <br />T Cells and macrophages<br />that the AIDS virus<br />infects<br />GMP<br />HSC<br />Macrophages<br />Erythrocytes platelets<br />CMP<br />MEP<br />
  48. 48. DNA cleaving domain<br />Zinc finger nucleases to disrupt the CCR5 gene<br />Zinc fingers target<br />specific DNA <br />sequences. The attached<br />nucleases chop the DNA.<br />DNA binding domain<br />ZFNs bind to the CCR5 gene<br />They cut the CCR5 gene<br />The cell repairs this break, but in a way that also destroys the CCR5 gene<br />
  49. 49. Pre-clinical testing<br />Human hematopoietic stem cells<br />Treat with CCR5 ZFNs<br />Transplant into special ‘NSG’ mice<br />HIV-1<br />Human T cells in mouse blood<br />HIV Infection<br />Day -1<br />Day 0<br />Months 2 - 4<br />
  50. 50. ZFN-treated HSC generate human cells in the mice that are HIV-resistant<br />Ctrl. HSC<br />HIV-1infected<br />ZFN HSC<br />CD4 T cells<br />ZFN<br />Ctrl.<br />Ctrl.<br />CD8<br />Human cells killed by HIV-1 infectionin untreated mice<br />thymus<br />CD4<br />CD8<br />0 2 4 6 8 <br />spleen<br />weeks post-HIV infection<br />CD4<br />CD45<br />lung<br />Human cells are normal in ZFN-treated mice<br />CD14<br />SSC<br />Gut mucosa<br />CD3<br />Holt et al. Nat Biotechnol. 2010 Aug;28(8):839-47<br />
  51. 51. Other USC Bioscience Interdisciplinary Initiatives<br />Neuroscience<br />Biomedical Nanoscience<br />Clinical and Translational Sciences Institute<br />Funded by NIH $60 million to facilitate translational research<br />

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