(Stem) cells to treat type 1 diabetes
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1 (Stem) cells to treat type 1 diabetes Prof. Robert Hilbrands Diabetologist - Nephrologist Diabeteskliniek UZBrussel
2 Type 1 diabetes Insulitis = inflammatory infiltrate involving Ilsets of Langerhans *Willy Gepts, Diabetes titel
3 Introduction insulin 3 titel
4 Introduction Type 1 Diabetes Auto-immunity Insulin Glycaemic instability Hypoglycaemia 4 titel
5 Introduction Beta Cell Replacement Therapy Auto-immunity Insulin Glycaemic instability Hypoglycaemia allogenic donor Potentially curative treatment 5 titel
6 Introduction Beta Cell Replacement Therapy Auto-immunity Allo-immunity Insulin allogenic donor Continuous Immunosuppression Required 6 titel
7
8 Islet Beta-Cell Transplantation BEFORE Beta Cell Transplantation AFTER Beta Cell Transplantation Basal C-peptide 0.5 ng/ml P. Gillard et al Diabetes Care. 2013
9 Islet Beta-Cell Transplantation Age and long-term graft function Age yrs yrs Basal C-peptide > 0.5 ng/ml Mean IQR3 Longest 3,3 yrs 5,0 yrs 8,7 yrs 4,2 yrs 5,9 yrs 14,1 yrs > 2 M Beta /kg; ATG MMF TAC
10
11 Problematic hypoglycemia Definition: Two or more episodes per year of severe hypoglycemia or One episode associated with impaired awareness of hypoglycemia, extreme glycemic lability or major fear and maladaptive behavior
12 Islet transplantation is an option! Clinical routine CSII: continuous SC insulin infusion SAP: sensor augmented pump LGS: low-glucose supsend
13 Patients Type 1 Diabetes Preclinical Patient Donor cel Tx Allo 1st insulin independence: 2000 Preclinical = research in animal models Tx = Transplantation
14 Introduction Potential cure for type 1 diabetes Limited supply Large scale sources Immunosuppression Immune protection Tolerance induction 14 titel
15 Stem cells 15 titel
16 Embryonic stem cells 16 titel
17 17 titel
18 Lessons from mother nature MODY 4 (PDX-1) 18 titel
19 Nat. Biotech 2005 and titel
20 How to make a beta cell from hesc D Amour et al.nat. Biotech titel
21 2008 Nat. Biotech titel
22 huesc-derived stage 4- pancr. endoderm (ViaCyte-Inc) cells encapsulated in ViaCyte s Encaptra Device vc SC implant in NSG mice Macroencapsulation Markers Functional Beta Cell Mass In vivo 50 weeks : - basal glycemia of human - hu-c peptide, glucose responsiveness T. Robert et al, Stem Cell Reports, titel
23 Preclinical studies In vitro In vivo T. Robert et al, Stem Cell Reports, titel
24 Preclinical studies SAFETY IMMUNITY Motté E. et al titel
25 Encapsulation Immune response Protects but does NOT prevent immune reactivity!!
26 Encapsulation Protection allo- & autoimmunity Protection innate immunity Support Vascularization Barrrier that avoids migration of cells with uncontroled growth With or without immunesuppression and anti-inflammatory strategies (systemic/local) Subcutaneous implantation 26 titel
27 Directed differentiation into fully functional beta cell from ESC/iPSC Cell, titel
28 Alternative Cell Sources directed differentiation and reprogramming Pagliuca, Melton Development, titel
29 Patients Type 1 Diabetes Preclinical Patient Donor cel Tx Allo Preclinical Patiënt Embryonic stem cell Tx Allo 1st insulin independence: 2000 Preclinical = research in animal models Tx = Transplantation
30 Today USA, Canada and Belgium 30 titel
31 Clinical trial - endpoints SAFETY Survival Maturation In vivo function 31 titel
32 Somatic cells Induced Pluripotent Stem Cells (ipsc) Embryonic stem cells Autologous Allogeneic Immunity 32 titel
33 Patients Preclinical Patient Preclinical Patiënt Preclinical Patiënt Type 1 Diabetes Donor cel Tx Allo Embryonic stem cell Tx Allo Induced pluripotent stem cell Tx Auto Identical twins 1 diabetic 1 non-diabetic Preclinical = research in animal models Tx = Transplantation
34 Personalized medicine Induced pluripotent stem cells (ipsc) Autologous origin BUT economics of scaling up personalized therapy challenging (i.e. quality/safety controls) Pragmatic approach bank of ipsc lines Autoimmune response remains! Fairchild P, Nat. Rev Immunology 2010, p titel
35 TODAY
36 Future
37 EU Horizon 2020 San Raffaele Hospital Lorenzo Piemonti Leiden Univ Bart Roep Collaborators Brussels Free University-VUB University Hospital Brussels Daniel Pipeleers Krista Suenens and team animal studies Ines De Mesmaeker, Thomas Robert Geert Stange and lab team Zhidong Ling and staff Beta Cell Bank Frans Gorus and team clinical chemistry Bart Keymeulen, Pieter Gillard, Daniel Tulleneers, Robert Hilbrands, Freya Van Hullle Diedert De Paep, and teams diabetes clinic in Brussels and Kath. Univ. Leuven ViaCyte, San Diego Evert Kroon Nestle Inst Health Sci Ed Baetge Marine Kraus
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