Cell Therapy for Diabetes: Generating Functional Islets from Human Exocrine Tissue
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1 Cell Therapy for Diabetes: Generating Functional Islets from Human Exocrine Tissue Kevin Docherty University of Aberdeen ELRIG Drug Discovery 2016 ACC Liverpool 14 th October 2016
2 Autoimmune destruction of beta cells in islets of Langerhans Insulin deficiency Seldom overweight Often young Decreased beta cell mass Insulin resistance Often overweight Older
3 Type 1 Diabetes 5 in 1000 affected in UK Commonest age of onset years old Males and females equally affected Symptoms urinary frequency, thirst, tiredness, weight loss 25% of children with diabetes 'seriously unwell before diagnosed Reliant on insulin injections
4 Advances in Therapy for Type 1 Diabetes Fast acting and long-acting insulin (analogues) Insulin pumps Islet transplantation (directed at Impaired Awareness of Hypoglycaemia)
5 Scottish Islet Isolation Centre Opened in 2010 Pancreas perfused with enzymes Placed in chamber with ball bearings Islets (stained red) are released from exocrine tissue
6 Islets are Purified by Centrifugation An islet prep (~ 600,000 islets)
7 First Islet Transplant in Scotland in February 2011
8 T r a n s p la n t s Summary of Islet Transplantations in UK 1 April December * p a t ie n ts o n w a itin g lis t * * * * 2 0 * * * y e a r Scotland's transplants made up 61% of the entire UK transplants in last two years Not enough donor organs to meet need Data from Shareen Forbes
9 Challenges in Islet Transplantation Two or three donors required per recipient Available donors would meet ~1% of demand Graft deteriorates with time Need for alternative sources of islets for transplantation
10 Alternative Sources of Islets for Transplantation 1. Pluripotent cell-derived islets. Viacyte. Clinical trials. 2. Reprogrammed (transdifferentiated) adult tissue.
11 Stem Cell Derived Islets are in Clinical Trials Viacyte Ltd Encapsulated Cells are Implanted under the Skin Trial Details The purpose of this trial is to test if VC-01 can be implanted subcutaneously in subjects with Type 1 Diabetes and maintained safely for two years. Start September 2014 End August 2017
12 Direct Reprogramming from Adult Tissue
13 Reprogramming Exocrine Tissue Towards Islets Reprogramming (7-10 days) Exocrine Tissue Reprogrammed Islets
14 Exocrine Clusters are Cryopreserved ~ 1% dithizone positive single cells (n = 95) 300,000 exocrine clusters per vial
15 In Adherent Culture Human Exocrine Cells Dedifferentiate Day 0 Day 2 Day 4 Day 6 50 µm 50 µm 50 µm 50 µm Day 8 Day 10 Day 12 Day µm 50 µm 50 µm 50 µm
16 Dedifferentiating Human Exocrine Cells Co-Express Epithelial and Mesenchymal Markers Day 2 Day 4 Day 10 Day 18 CK19 Vimentin DAPI Amylase Vimentin DAPI
17 Dedifferentiating Exocrine Cells Undergo EMT Epithelial to Mesenchymal Transition
18 Genetic Lineage Tracing of Amylase Positive Cells Confirms EMT Ad-Amyl-Cre dsred Lenti-dsRed Day 4 Day 6 Day 7 Day 10 VIM dsred CK19
19 Using Pdx1, MafA, Ngn3 and Pax4 (PMNPx) to Drive Exocrine Acini to Islets E8 Ngn3 Acinar Pax4 Arx Pdx1 MafA Oct4/Nanog + Sox17 + Hnf + Pdx1 Ngn3 Multihormonal ES cells Definitive Endoderm Posterior foregut Fore Mid Pancreatic endoderm ST P LG LV P Islet percursors IA1 Islet of Langerharns β cell Insulin + Pdx1 + MafA +
20 Exocrine to Endocrine Transdifferentiation Pdx1 (P) MafA (M) Ngn3 (N) Pax4 (Px) Adenoviruses RT/qPCR ICC Glucagon Glucagon 100 µm Glucagon 25 µm
21 Suppression of EMT was Crucial in Generating Insulin Positive Cells Ex vivo ROCK/TGF-β inhibitors MafA Pdx1 Pax4 Ngn3 Exocrine fraction EMT inhibition 3 days Reprogramming 7 days Beta cells 10 days Diabetes 62: , 2013
22 But Insulin Expression Very Low RT/qPCR 0.2%
23 Regulatory Circuit Between ARX and Pax4 Endocrine progenitor Pax4 Arx β-cell α-cell
24 Relative Expression ARX Inhibition Enhances Insulin Expression Laminin Laminin Laminin TGF-β / Rock inhib 4TFs + BEN siarx REP Time (days) REP + siarx RT/qPCR
25 Protocol for Generating Functional Islets from Exocrine Pancreas Towards the Clinic Plating EMT inhibition Reprogramming Time 10 (days) Laminin-coated plates/ RPMI/ 5 mm Glucose/Zinc Stage 1 No addition Stage 2 SB Y2 Az NaBu Stage 3 4TFs Stage 4 BEN Stage 5 BEN + siarx Publications describing method Lima et al. (2013) Diabetes 62, Lima et al. (2016) PLoS One 11: e Patents W02015/ A1 and WO2015/ A1 Technology licensed to Islexa Ltd for clinical development
26 To be Therapeutically Relevant REP-Islets Must 1. Make therapeutic amounts of insulin (fully processed proinsulin to insulin) 2. Function like adult human islets (first and second phase secretory response to glucose) 3. Look like human islets (ICC and flow cytometry) 4. Be phenotypically stable (animal studies)
27 Exocrine Derived REP-Islets Insulin Content pmol/ug protein pmol/ug protein ProInsulin ProInsulin 250 Insulin Insulin 200 C-Peptide C-Peptide N/A N/A REP REP REP + siarx ISLETS REP + siarx ISLETS
28 Exocrine Derived REP- Islets - Morphology Form Islet-Like Clusters Expressing Insulin and Glucagon Donor Islets REP-Islets Glucagon - green Insulin - red Nuclei - blue
29 Exocrine Derived REP-Islets - Animal Studies Normalise Blood Glucose Levels in STREP Diabetic Mice STZ Tx Nephrectomy Kidney Capsule
30 Blood Human C-peptides Animal Studies REP-Islets are Phenotypically Stable 18 days 50 days
31 Conclusions Plating EMT inhibition Reprogramming Time 10 (days) Laminin-coated plates/ RPMI/ 5 mm Glucose/Zinc Stage 1 No addition Stage 2 SB Y2 Az NaBu Stage 3 4TFs Stage 4 BEN Stage 5 BEN + siarx Therapeutic amounts of insulin; fully functional islet-like Twelve days GMP amenable No pluripotency issues Final product is a mixture of islets and MSCs One transplantable unit - ~ 1-2 billion cells transplantable units from one donor pancreas
32 Next Steps Technology and commercial development of the protocol will be conducted through Islexa Ltd. Islexa was created by the Cell and Gene Therapy Catapult and University of Aberdeen in 2016 Development includes evaluation of an expansion step to increase the number of clinical doses from each donor pancreas, to enable treatment of thousands of type 1 diabetic patients per year Further information
33 Acknowledgements Aberdeen Maria João Lima Hilary Docherty Laura Ferguson Kenny Muir Edinburgh John Casey Shareen Forbes John Campbell Marc Turner Brussels Harry Heimberg Yves Heremans STMTI/
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