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JDRF Research Update Richard Insel, M.D. Executive Vice President, Research

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JDRF Research Update Richard Insel, M.D. Executive Vice President, Research

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    3. JDRF FY 2004: Geography

    4. To Cure Type 1 Diabetes = Developing Curative or “Cure” Therapeutics or Interventions Islet transplantation or regeneration Immune tolerance or immunoregulation Complications Combination therapy will be required!

    8. JDRF Five-Year Bold and Significant Outcomes on the Path to Cure Type 1 Diabetes Perform islet transplantation without chronic immunosuppression Create a “universal donor” source of insulin-secreting cells for transplantation Regenerate the body’s own beta cells Prevent type 1 diabetes or reverse type 1 diabetes in new-onset disease by maintaining or restoring immune tolerance Predict, prevent, reverse complications Perfect a closed loop artificial pancreas

    9. Islet Transplantation

    12. Edmonton Protocol

    15. Islet Transplantation: Source Improvements in islet isolation and preservation- culturing islets before infusion Single cadaver donor pancreas New sources for islets: in-vitro growth of human islets, porcine islets, embryonic and adult stem cells, living related islets Non-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusionNon-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusion

    19. As several scientists have pointed out, we know of only one definite path to create a beta cell and that is the path nature takes in going from an embryonic stem cell. So we must vigorously pursue this avenue of research in addition to searching for any possible adult stem cells that could be coaxed to become beta cells.As several scientists have pointed out, we know of only one definite path to create a beta cell and that is the path nature takes in going from an embryonic stem cell. So we must vigorously pursue this avenue of research in addition to searching for any possible adult stem cells that could be coaxed to become beta cells.

    20. JDRF Stem Cell Research $9M in FY04: $5M ES, $3M adult, $1M animal stem cells Partnerships: Sweden, UK, France, Finland, Canada, Australia, Singapore Animal-free hES lines being derived D. Melton derived 28 new stem cell lines with JDRF and HHMI funding

    22. Islet Transplantation Requires Chronic Immunosuppression to Prevent Alloimmune (Foreign) or Autoimmune Rejection Non-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusionNon-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusion

    23. Immune Tolerance or Immunoregulation Non-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusionNon-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusion

    24. Need to Replace Chronic Immunosuppression with Immune Tolerance or Immunoregulation to Prevent Islet Rejection Non-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusionNon-heart beating donors Age limits to include over 65 Obese Infusion protocols- prevent bleeding at site on infusion

    26. Beyond Edmonton: JDRF Centers Alabama – NHP (monkey) islet transplants without chronic immune suppression and stable for >5 years Pennsylvania – NHP islet transplants without chronic immune suppression Edmonton, Emory – NHP islet transplantation without lifelong drugs Minnesota – Plans first ‘drug withdrawal’ clinical trial Harvard– Power Mix in NHP w/o immune suppression Harvard– Novel approach to “mixed chimerism” Deleted Birmingham in second bulletDeleted Birmingham in second bullet

    27. Five-Year Bold and Significant Outcomes on the Path to Cure Type 1 Diabetes Performing islet transplantation without chronic immunosuppression Creating a “universal donor” source of insulin-secreting cells for transplantation Regenerating the body’s own beta cells Preventing type 1 diabetes or reversing type 1 diabetes in new-onset disease by maintaining or restoring immune tolerance Predicting, preventing, reversing complications Perfecting a closed loop artificial pancreas

    28. Regeneration: Why now? Normal turnover of beta cells Physiological increase in beta cells in obesity and pregnancy Regeneration occurs in animal models of diabetes, pancreatic injury- ? Mechanisms Evidence of residual islets and function in type 1 diabetes

    30. Can beta cell regeneration occur in established Type 1 Diabetes? Pancreatic beta cell regenerative capacity may remain clinically masked by Poor glycemia control and/or other metabolic factors Residual anti-beta cell specific autoimmunity Increase by directing careful attention to: Glycemia and lipid control Control of anti-beta cell autoimmunity Delivering factors that promote beta cell neogenesis, replication, or survival in vivo

    32. Regeneration Therapeutics: Application Established Diabetes- restore beta cells Prediabetes- maintain beta cell reserves of genetically identified high risk subjects Early application to islet transplantation

    33. Regeneration Research: Interim Application to Islet Transplantation Islet transplantation setting can be used to test regeneration discoveries, and in turn, interim regeneration discoveries and developments can be applied to benefit islet transplantation Enhance success of current islet transplant protocols Grow islets from a single donor organ to transplant multiple recipients Safely transplant adequate number of islets from a living-related donor

    34. Regeneration: Clinical Trials GLP-1/Exendin-4/Exenatide-4/Incretin mimetics (Glucagon-Like Peptide-1) C Greenbaum- At-risk K Herold- New onset diabetes with anti-CD3 D Harlan- Established type 1 diabetes with immunosuppression C Ricordi- Islet transplantation setting (Amylin) EGF and Gastrin; GLP-1 and Gastrin (Transition Therapeutics/NovoNordisk) INGAP (Islet NeoGenesis Associated Protein) (GMP/Procter and Gamble Pharmaceuticals)

    35. JDRF Regeneration Program: “Regeneration of Beta Cell Function” Goal driven program with milestones Team Science- interdisciplinary, interactive teams from diverse scientific fields and from both academia and industry, attract new scientists (to date- 17 scientists in the program) Fast-track Accountability Focused on solving problems

    36. Five-Year Bold and Significant Outcomes on the Path to Cure Type 1 Diabetes Performing islet transplantation without chronic immunosuppression Creating a “universal donor” source of insulin-secreting cells for transplantation Regenerating the body’s own beta cells Preventing type 1 diabetes or reversing type 1 diabetes in new-onset disease by maintaining or restoring immune tolerance Predicting, preventing, reversing complications Perfecting a closed loop artificial pancreas

    37. Clinical Interventions in Type 1 Diabetes

    38. Clinical Interventions in Type 1 Diabetes

    39. Clinical Interventions in Type 1 Diabetes

    41. Treatment of New Onset Type I Diabetes with Non-Mitogenic anti-CD3 Antibody 3 Clinical Trials completed to date JDRF sponsored- European Phase II trial – Multicenter – Placebo Controlled- 80 patients with recent onset Type I diabetes (<4 weeks insulin treatment)- one week antibody treatment Outcome- preservation of insulin secretion and secondarily decreased insulin dose requirements at 6, 12, 18, 24 months after treatment Long term effects from activation of immunoregulation

    42. Treatment of New Onset Type I Diabetes with Non-Mitogenic anti-CD3 Antibody: Next Steps Prolong the therapeutic effect Combine with regeneration therapeutics- e.g. Exenatide Apply to high risk prediabetes to prevent onset of Type 1 diabetes

    43. Five-Year Bold and Significant Outcomes on the Path to Cure Type 1 Diabetes Performing islet transplantation without chronic immunosuppression Creating a “universal donor” source of insulin-secreting cells for transplantation Regenerating the body’s own beta cells Preventing type 1 diabetes or reversing type 1 diabetes in new-onset disease by maintaining or restoring immune tolerance Predicting, preventing, reversing complications Perfecting a closed loop artificial pancreas

    44. Recent work by Michael Brownlee’s group suggests that overproduction of mitochondrial superoxide is the principle pathogenic insult underlying the activation of these four major pathways to hyperglycemia induced injury. This may explain why single pathway inhibitors have not worked well in clinical trialsRecent work by Michael Brownlee’s group suggests that overproduction of mitochondrial superoxide is the principle pathogenic insult underlying the activation of these four major pathways to hyperglycemia induced injury. This may explain why single pathway inhibitors have not worked well in clinical trials

    45. Common Pathways in Complications

    46. Research Management Acceleration Strategy Focus on Cure therapeutic Goals Leverage/Coordinate/Integrate all funders of type 1 research Rapid response to opportunities Translate 30 years of basic science discovery to commercial application for development of therapeutics Address the funding gap between basic science and clinical development, while continuing to support innovative discovery

    52. Questions

    53. Research Has Already Significantly Improved the Lives of People with Diabetes DCCT – we now know how to reduce the threat of complications Vast improvement in monitors/insulin delivery Laser Treatment for Retinopathy Statins to reduce risk of heart disease >400 people “cured” by islet transplantation Several successful experimental treatments of complications Several successful experimental treatments that have stopped progression of diabetes

    54. Recent New Research Developments Better understanding of immunology of type 1 diabetes Better understanding of pathogenesis of complications Improved immunosuppression and new approaches to induce immune tolerance New insights into genetics of diabetes

    55. Important Diabetes Discoveries and Developments in Last Decade Success of Islet Transplantation Ability to predict accurately risk of diabetes (genetics, antibodies) Interventions in new-onset diabetes to preserve beta cells DCCT study insights of importance of glucose control to prevent complications Improvement in glucose monitoring

    57. Auto-immunity Intervention Trials Clinical Anti-CD3 Phase II clinical trial – New York/Belgium IL2 and rapamycin in new onset – Joslin Anti-CD3 plus Exendin4 – New York/San Francisco MMF + daclizumab – Denver Pre-clinical Anti-CD20 – Penn Thymoglobulin – Genzyme

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