Could Science Help Diabetes Patients Become Their Own Insulin Donors?
What if a diabetes patient’s own cells—taken from his or her own adult tissue—could be made to create insulin, secreting the compound whenever needed? This specific type of cell therapy is a form of what has been called “autologous cell replacement.” Diabetes now affects about 285 million people globally, about 6.4 percent of the global population. The World Health Organization predicts that this figure is slated to increase to 366 million by the year 2030. According to the American Diabetes Association, 1.9 million fresh cases of diabetes were diagnosed in people aged 20 years and older in 2010, an estimated 7.0 million Americans have undiagnosed diabetes, and an additional 79 million have pre-diabetes. Approximately 25.8 million children and adults in the United States—8.3% of the population—have diabetes. Various types of treatment for diabetes are available today, but they all present specific drawbacks to the patient. For example, insulin therapy can trigger a host of conditions from weight gain to hypoglycemia, and its administration must be continuously controlled and monitored by the patient.
A new approach to this problem is now being pursued by a small biotech company named Orgenesis (http://www.orgenesis.com), which initiated its program by posing the following question: What if a diabetes patient’s own cells—taken from his or her own adult tissue—could be made to create insulin, secreting the compound whenever needed? This specific type of cell therapy is a form of what has been called “autologous cell replacement.” For years, the idea of harvesting stem cells and re-implanting them into one’s own body to regenerate organs and tissues has been researched and embraced in animal models. The approach being pursued by Orgenesis comprises a number of steps. First, a standard liver biopsy is extracted from a diabetes patient in a clinical center and then sent to a laboratory. In the lab, the liver cells are initially propagated in vitro. A subset of these cells are then manipulated with a therapeutic agent (i.e., the “master regulator” PDX-1 that oversees pancreas development, or additional pancreatic transcription factors in adenovirus-vector) that transforms a subpopulation of liver cells into different cells with pancreatic islet phenotype and function. The therapeutic agent initiates a cascade of events, transforming the cells into “autologous insulin-producing” (AIP) cells.
These cells now act in a similar fashion to the beta cells that create insulin in the pancreas of healthy people. Insulin is not only produced, but also stored and secreted in a glucose-regulated manner. At the clinical center, the freshly formed AIP cells are then transplanted in a standard infusion procedure back to the patient’s liver where they secrete insulin. Since the initial liver cells were extracted from the patient, there is no possibility of rejection. Orgenesis has successfully tested its technology in mice, rats and pigs, and is working toward initiating clinical trials in humans. The surprising capacity to activate pancreatic lineage in the liver was initially demonstrated in mice by systemic PDX-1 administration using recombinant adenovirus gene delivery. PDX-1 plays a dual and central role in regulating both pancreas organogenesis in embryo and beta cell function in adults. The capacity of PDX-1 to direct pancreas development has been shown in mature fully differentiated liver in vivo, both in mice and in Xenopus, possibly via a process called trans -differentiation. This describes an irreversible switch of one type of differentiated cell into another differentiated cell.
AIP therapy appears to be safer than other options, since it does not change the host genome but only changes the set of expressed genetic information that appears to be highly specific to the reprogramming protocol. In addition, no human organ donations or embryo-derived cells are needed. This type of therapy, if shown to be usable in clinical trials, would present several advantages over alternative insulin-dependent diabetes therapies now being studied.
First, it frees the patient from having to monitor of blood glucose levels, undergo numerous insulin injections and watch food intake and exercise on a daily basis. Indeed, the body itself is now continuously regulating blood glucose levels. In addition to avoiding the chance of autoimmune rejection, the procedure is only minimally invasive. In brief, the use of adult human liver cells for generating functional insulin-producing tissue might pave the way to autologous implantations, thus allowing the diabetic patient to be the donor of his or her own insulin-producing tissue.
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