Geron Corporation has reported that its scientists and collaborators at the University of Alberta have differentiated human embryonic stem cells (hESCs) into islet-like clusters (ILCs) that secrete insulin in response to elevated glucose levels. The studies demonstrate the feasibility of producing therapeutic cell types from hESCs for the treatment of diabetes.
To be published in the August issue of Stem Cells, the paper describes studies showing how the researchers differentiated hESCs into cell clusters containing the main cellular components of the islets of Langerhans.
The islets of Langerhans are structures in the pancreas that are responsible for regulating and producing insulin in response to changing glucose concentrations and are targets for autoimmune destruction or dysfunction in Type I Diabetes.
“These studies show that the islet-like clusters contain the major cellular components of islets and are sensitive to glucose, the key sugar to which they must respond to be therapeutically beneficial,” stated Anish Majumdar, Ph.D., the senior author of the paper. “Our major goal moving forward is to improve the purity, yield and maturational status of these cells to induce normoglycemia in animal models of diabetes.”
Geron Corporation was granted U.S. Patent No. 7,033,831 in April 2006 covering the production of insulin-secreting cells from hESCs as well as two U.K. patents covering similar production methods. Geron also has a worldwide exclusive commercial license covering hESC-derived islets from the Wisconsin Alumni Research Foundation.
Geron’s scientists and collaborators produced ILCs containing individual cells types that express insulin, glucagon and somatostatin, three of the major hormones produced by islet ß, a and d cells, respectively.
Further analysis of the insulin-producing cells indicates they also produce c-peptide, a peptide cleaved upon secretion of the precursor of insulin, indicating that insulin was actually produced, and not absorbed, by the cells. Approximately 2%-8% of the differentiated cells contain insulin and c-peptide and their insulin content was higher than that of fetal islets.
The ILCs functioned to secrete insulin in response to elevated glucose levels. Cells within the ILCs contained secretory granules characteristic of those seen in islet ß cells. In cell culture, the ILCs produced c-peptide and insulin when exposed to higher concentrations of glucose with the kinetics of an immature islet.
The protocol to produce the ILCs drives hESCs through a series of cell culture steps that mimic the progressive differentiation stages during development of the pancreas in humans. Other pancreatic cell types resembling those of the exocrine pancreas were also observed during the differentiation process. The protocol does not utilize serum or feeder cells of any kind, underscoring the scalability of the process.
Originally developed at the University of Alberta, the Edmonton Protocol provides the proof of concept that transplantation of purified cadaveric islets can significantly reduce the need for insulin in patients with advanced Type 1 Diabetes. Problems limiting the accessibility of transplantation therapy for diabetes patients are the poor availability of organs from cadavers and the eventual failure of the grafts, which often require replacement and chronic immunosuppression.
“The Edmonton Protocol provides significant evidence that transplantation of primary islets can be used to successfully reduce the need for insulin in patients with Type 1 Diabetes,” said Thomas B. Okarma, Ph.D., M.D., Geron’s president and chief executive officer. “It is the work published today that demonstrates the potential of human embryonic stem cells to enable the ready availability of uniform, functional islet cells for therapeutic administration.”
Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure, diabetes and HIV/AIDS. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials.