Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy

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1 1 Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy Ole D. Madsen Senior Principal Scientist Diabetes Biology Novo Nordisk A/S Honorary Professor in Diabetes Stem Cell Research University of Copenhagen

Madsen Senior Principal Scientist Diabetes Biology Novo

2 Agenda Diabetes and the Beta Cell. How to best preserve our beta cells? Role of Glp-1 and Insulin in beta cell homeostasis Cell based therapy Edmonton protocol Beta cells from stem cells

3 Diabetes - prevalence T1D: 5-10% of all cases T2D: 90-95% of all cases Diabetes currently affects 387 million people worldwide and this number is expected to rise to 592 million by death / 6 seconds (5.1 mill/yr) - ~2 newly diagnosed / 6 seconds (11 mill/yr) (latest edition of the IDF Diabetes Atlas)

expected to rise to 592 million by 2035 1 death / 6 seconds (5.

4 Diabetes a worldwide challenge Need for improved treatment modalities We must change this grim forcast! 4 1 death every 7seconds 5 2 new patients every 7 seconds

5 Lifetime cost of diabetes We must focus on prevention Control and Monitoring (20-30%) Medicines Complications (70-80%) Improved glycemic control reduce the risk of developing complications Future goal: - normalization of blood sugar to eliminate the risk of developing complications American Diabetes Association: Economic costs of diabetes in the US in Diabetes Care (2008) 31(3):

Future goal: - normalization of blood sugar to eliminate the risk of developing complications

6 Insufficient Mass of Functional -cells Cause Diabetes Diabetes; 2003 vol. 52 : ? T2D (obese) Obesity normoglycemia? T1.5D (LADA) Normal / normoglycemia Edmonton protocol Islet transplantation + immunotherapy T1D (autoimmune) Madsen, APMIS 2005

7 Regulation of functional Beta cell mass - role of glucose (in mice) Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) Cell death Glucose Glucose Glucose is required for pancreatic endocrine cell formation (Scharfmann et al JBC 2007) Glucose Replication Glucose activates synthesis of proteins which suppress a constitutive apoptotic program in beta cells (Pipeleers JCI 1996) Slide No Glucose is the mitogenic hormone regulating homeostatic functional Beta Cell mass (Ferrer 2011) Madsen, APMIS 2005

2007) Glucose Replication Glucose activates synthesis of proteins which suppress a constitutive apoptotic program in beta cells

8 Regulation of functional Beta cell mass - role of glucose (in mice) and insulin Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) Cell death Glucose Glucose Insulin receptors in -cells are critical for islet compensatory growth response to insulin resistance (Okada et al PNAS 2006) IR IRS2 Glucose Disruption of IRS-2 causes type 2 diabetes in mice (Withers et Nature 1998) + Insulin Replication Slide No Madsen, APMIS 2005

for islet compensatory growth response to insulin resistance (Okada et al PNAS 2006) IR IRS2 Glucose Disruption of

9 Regulation of functional Beta cell mass -role of Glp-1 Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) Cell death Slide no 9 JJ Holst Physiol Rev. 87(4): ; 2007 Glp-1 Glp-1 Hui et al, Diabetes 50: , 2001 Xu et al, Diabetes 48: , 1999 Hui et al, Endocrinology 144:1444; 2003 Glp-1 Replication Farilla et al, Endocrinology 143:4397; 2002 Slide No Rewiew: Drucker D J Endocrinology 2003;144: Madsen, APMIS 2005

87(4):1409-39; 2007 Glp-1 Glp-1 Hui et al, Diabetes 50:785-796, 2001 Xu et al, Diabetes 48:2270-2276, 1999 Hui et al,

10 Presentation title Date 10 Insulin + Glp1? Neo-formation Sensor of functional beta cell mass GSIS + incretin (Glp1) Cell death MST1 deletion protects against diabetes Nature Medicine Volume: 20, Pages: (2014) doi: /nm.3482 Glucose IR IRS2 Glucose MST1 Glucose + Insulin + Glp-1 Replication

Cell death MST1 deletion protects against diabetes Nature Medicine Volume:

11 HbA 1c over time DUAL trial Gough et al. Diabetologia 2013;56(Suppl. 1):S96(OR-219); Buse et al. Diabetes 2013;62(Suppl. 1):A Liraglutide (n=414) IDeg (n=413) IDegLira (n=833) HbA 1c (%) HbA 1C EOT -1.28% 7.0% -1.44% 6.9% Time (weeks) Mean values (±SEM) based on FAS and LOCF-imputed data; EOT = end of trial; p-values are from an ANCOVA --- ADA/EASD HbA 1c target <7.0%; AACE HbA 1c target 6.5% -1.91%* 6.4% *p< vs. IDeg and vs. Liraglutide

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) Mean values (±SEM) based on FAS and LOCF-imputed data; EOT = end of trial;

12 Insufficient Mass of Functional -cells Cause Diabetes window of prevention? Glp-1 + Insulin T2D (obese) Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune)

13 Insufficient Mass of Functional -cells Cause Diabetes window of prevention? Glp-1 + Insulin T2D (obese) Glp1 3mg Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune) April 22nd, 2015: Saxenda to be launched in USA for obesity treatment

14 14 Islet transplantation, a cure for diabetes? Naftanel MA, Harlan DM (2004) Pancreatic Islet Transplantation. PLoS Med 1(3): e58

15 Islet transplantation a real alternative Proof of principle: Cell therapy of T1D can restore euglycemia Before transplant. After transplant. Shapiro A.M.J et al.,n Engl J Med 2000;343: Patients with severe type 1 diabetes. Inadequate glycemic control despite insulin therapy Recurrent hypoglycemic episodes No detectable C-peptide levels Multiple islet infusions Glucocorticoid-free immunosuppression

16 Edmonton protocol, 5-year follow-up Islet transplantation has greatly improved the life quality of 68% after 1 year patients with severe type I diabetes by relieving glucose 40% after 2 years instability and problems with hypoglycaemia 22% after 3 years ~7.5% after 5 years; >80% C-pep+ *) Ryan et al. Five-Year Follow-Up After Clinical Islet Transplantation. Diabetes, (7): p *)No recurrence of hypo s

problems with hypoglycaemia 22% after 3 years ~7.5% after 5 years; >80% C-pep+ *) Ryan et al.

17 1 7 A stem cell to beta cell project is based on cutting edge science but with significant challenges ahead Vision To find a cure for diabetes Aspiration Strategic plan and timeline To develop a product that maintains a normal blood glucose level without insulin treatment To pursue opportunity for β cell replacement therapy based on stem cell technology

plan and timeline To develop a product that maintains a normal blood glucose level

18 Pluripotent stem cells, a potential source of beta cells for diabetes therapy Modified from Smith A. Annu. Rev. Cell Dev. Biol : Modified from Jensen et al. J Cell Physiol Jun;219(3):513-9

19 19 Project goal: To generate functional beta cells for replacement therapy as a treatment of diabetes Purification hescs Definitive Endoderm Pancreatic Endoderm Endocrine Progenitors Beta cell Source: Modified from Ole D Madsen & Palle Serup. Nature Biotechnology 24, (2006)

Endoderm Pancreatic Endoderm Endocrine Progenitors Beta cell Source:

20 Generation of definitive endoderm (DE), pancreatic endoderm (PE) and endocrine progenitors (EP) 20

21 Towards the generation of mature endocrine cells Slide no 21

22 Project goal: To generate functional beta cells for replacement therapy as a treatment of diabetes 22 Current focus Purification hescs Definitive Endoderm Pancreatic Endoderm Endocrine Progenitors Beta cell Source: Modified from Ole D Madsen & Palle Serup. Nature Biotechnology 24, (2006)

23 Encapsulation and transplantation

24 Reconstitution of functional beta cell mass (and BMI in obesity) Insufficient Mass of Functional -cells Cause Diabetes may strongly reduce risk for developing diabetes complications window of prevention? Glp-1 + Insulin T2D (obese) Glp1 3mg Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune)

25 State of the art Stem cell derived beta cells for cell thearpy: Presentation title Date Pancreatic progenitors Viacyte is in Phase 1/2 clinical trial with VC01 (pancreatic progenitor cells that require up to 4 months of in vivo maturation before mature beta cells develop and become functional) Viacyte is a J&J controlled biotech Mature beta cells formed in vitro cure diabetes in T1D mice (requires an O 2 rich device before going into man) Kieffer-lab Vancouver: Nat Bio publication Oct 2014 Melton-lab Harvard: Cell publication Oct 2014 Kieffer-lab collaborate with Betalogics (a J&J controlled biotech) T2D (Diet induced diabetes/obesity) Kieffer-lab: Stem Cell Reports Apr 2015

26 Presentation title A cure for diabetes is within reach after scientists developed a treatment that eliminates the need for sufferers to inject insulin. The therapy involves a one-off transplant of laboratory-grown pancreatic cells, which scientists have finally succeeded in producing in large enough volumes to be able to treat patients. The cells worked normally for many months when implanted into mice, and the first human patients should undergo the treatment in the next few years Date 2 6 The advance is the culmination of 23 years of research by Doug Melton, pictured here with his wife Gail O'Keefe

27 State of the art 2 7

28 State of the art 2 8

29 Breakthroughs in the treatment of diabetes! 1920 J.L., Dec 15, 1922 Feb 15, 1923 Life saving treatment of patients with type 1 diabetes Unlimited supply Improved glucose control 2000 Improved -cell function The future: Regeneration of functional -cell mass Discovery of insulin Recombinant human insulin Insulin analogues GLP-1 Treatment Prevention Cure

30 THANK YOU FOR YOUR ATTENTION

31 Presentation title Date 31 No dreamer is ever too small no dream is ever too big

Regenerative Medicine : A Promising Approach In Overcoming Diabetes As An Increasing Economic Health Burden

Journal of Emerging Economies and Islamic Research www.jeeir.com Regenerative Medicine : A Promising Approach In Overcoming Diabetes As An Increasing Economic Health Burden Nafeeza Mohd Ismail a, Renu