18 research outputs found
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How to make a functional β-cell
Insulin-secreting pancreatic β-cells are essential regulators of mammalian metabolism. The absence of functional β-cells leads to hyperglycemia and diabetes, making patients dependent on exogenously supplied insulin. Recent insights into β-cell development, combined with the discovery of pluripotent stem cells, have led to an unprecedented opportunity to generate new β-cells for transplantation therapy and drug screening. Progress has also been made in converting terminally differentiated cell types into β-cells using transcriptional regulators identified as key players in normal development, and in identifying conditions that induce β-cell replication in vivo and in vitro. Here, we summarize what is currently known about how these strategies could be utilized to generate new β-cells and highlight how further study into the mechanisms governing later stages of differentiation and the acquisition of functional capabilities could inform this effort.Stem Cell and Regenerative Biolog
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Long term Glycemic Control Using Polymer Encapsulated, Human Stem-Cell Derived β-cells in Immune Competent mice
The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in diabetic patients1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but are limited by the adverse effects of lifetime immunosuppression and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose responsive mature β-cells derived from human embryonic stem cells; called SC-β, these cells may represent an unlimited human cell source for pancreas replacement therapy4. Strategies to address the immunosuppression concern include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier5,6. However, clinical implementation has been challenging due to host immune responses to implant materials7. Here, we report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells. SC-β cells were encapsulated with alginate-derivatives capable of mitigating foreign body responses in vivo, and implanted into the intraperitoneal (IP) space of streptozotocin-treated (STZ) C57BL/6J mice. These implants induced glycemic correction until removal at 174 days without any immunosuppression. Human C-peptide concentrations and in vivo glucose responsiveness demonstrate therapeutically relevant glycemic control. Implants retrieved after 174 days contained viable insulin-producing cells
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A simple tool to improve pluripotent stem cell differentiation
We describe a method to help overcome restrictions on the differentiation propensities of human pluripotent stem cells. Culturing pluripotent stem cells in dimethylsulfoxide (DMSO) activates the retinoblastoma protein, increases the proportion of cells in the early G1 phase of the cell cycle and, in more than 25 embryonic and induced pluripotent stem cell lines, improves directed differentiation into multiple lineages. DMSO treatment also improves differentiation into terminal cell types in several cell lines.Stem Cell and Regenerative Biolog
Differentiated human stem cells resemble fetal, not adult, β cells
Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorted insulin-expressing (INS[superscript +]) cells derived from three independent hPSC lines, human fetal pancreata, and adult human islets points to two major conclusions: (i) Different hPSC lines produce highly similar INS[superscript +] cells and (ii) hPSC-derived INS[superscript +] (hPSC-INS[superscript +]) cells more closely resemble human fetal β cells than adult β cells. This study provides a direct comparison of transcriptional programs between pure hPSC-INS[superscript +] cells and true β cells and provides a catalog of genes whose manipulation may convert hPSC-INS[superscript +] cells into functional β cells.Leona M. and Harry B. Helmsley Charitable TrustHarvard Stem Cell InstituteNational Institutes of Health (U.S.) (Grant 2U01DK07247307)National Institutes of Health (U.S.) (Grant RL1DK081184)National Institutes of Health (U.S.) (Grant 1U01HL10040804
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259-OR: Stem Cell–Derived, Fully Differentiated Islet Cells for Type 1 Diabetes
Cadaveric islet transplantation can achieve glycemic control in T1D, but cadaveric islet quantity and quality are limiting. We report the first patient-administered VX-880, an investigational allogeneic stem cell–derived, fully differentiated, pancreatic islet cell replacement therapy. A 64-year-old male with a 40-year history of T1D complicated by impaired awareness of hypoglycemia with 5 severe hypoglycemic events (SHEs) the year before VX-880 was receiving 34U insulin/day at baseline (HbA1c 8.6%; undetectable fasting and stimulated C-peptide) . After a single VX-880 infusion at half target dose, fasting C-peptide was detected by Day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel. At Day 90, robust increases in fasting and stimulated C-peptide, improved glycemic control, and a substantial reduction in exogenous insulin administration were observed and continued to improve through last time point assessed (Table) . VX-880 was generally safe and well tolerated; most AEs were mild or moderate and consistent with immunosuppression. The most common AEs were SHEs (not serious or related to VX-880) , which occurred in the perioperative period. There was 1 serious AE of rash (mild, unrelated to VX-880) , which resolved. These unprecedented results are the first evidence that stem cell–derived islets can restore insulin production and glucose control in T1D. The study continues to enroll and dose patients
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Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes
The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species.
•Reaggregated human SC islets display glucose-stimulated insulin secretion in vitro•Conformal-coated human SC islets displayed physiological insulin secretion•Conformal-coated human SC islets in mice reversed diabetes to human euglycemic levels
Scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Islet encapsulation may eliminate the need for chronic immunosuppression. Conformal coating seeks to overcome limitations of traditional microencapsulation. Transplantation of conformal-coated stem cell-derived islets might extend the applicability of islet transplantation to a larger cohort of patients
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836-P: Glucose-Dependent Insulin Production and Insulin-Independence in Type 1 Diabetes from Stem Cell–Derived, Fully Differentiated Islet Cells—Updated Data from the VX-880 Clinical Trial
VX-880 is an investigational allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy being evaluated in a phase 1/2 clinical trial in patients with T1D and impaired hypoglycemic awareness and severe hypoglycemia. The phase 1/2 trial has three parts: Part A in which 2 patients are enrolled sequentially and receive half the target dose (presented at ADA 2022), Part B in which 5 patients are enrolled sequentially and receive the target (full) dose, and Part C where 10 patients are enrolled concurrently and receive the target (full) dose. The first two patients infused with VX-880 at half the target dose (in Part A) had restored insulin production and glucose control. One of these patients achieved and has maintained insulin independence, defined as at least one week off exogenous insulin, HbA1C ≤7%, post-prandial serum glucose at 90 minutes ≤180 mg/dL, fasting serum glucose ≤126 mg/dL, and fasting or stimulated C-peptide ≥166 pmol/L (latter 3 measured during mixed-meal tolerance test). The safety profile was consistent with the immunosuppressive regimen used in the study and the perioperative period. Part B is now fully enrolled and multiple patients have been dosed with the full (target) dose. Longer-term data on both patients in Part A and new data on patients who received the full (target) dose in Part B will be provided in the presentation. These results are the first from a clinical trial of allogeneic, fully differentiated, insulin producing, stem cell-derived islets which has demonstrated the potential to restore insulin production and glycemic control and provide insulin independence in patients with T1D. Disclosure T.W.Reichman: Consultant; Sernova, Corp., Research Support; Vertex Pharmaceuticals Incorporated. J.L.Shih: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. D.Melton: None. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Consultant; Vertex Pharmaceuticals Incorporated, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bristol-Myers Squibb Company, Adaptive Biotechnologies, Merck & Co., Inc., Tessera, Novartis. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. J.F.Markmann: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). M.Wijkstrom: None. S.Paraskevas: None. B.Bruinsma: Employee; Vertex Pharmaceuticals Incorporated. G.Marigowda: Employee; Vertex Pharmaceuticals Incorporated