MIAMI, FL – February 19, 2019 — Researchers have been advancing methods to generate insulin-producing beta cells from pluripotent stem cells (PSC) for the clinical treatment of type 1 diabetes (T1D). However, transplantation of these immature cells into patients poses substantial risks, namely the development of tumors (teratomas) and the growth of these stem cells into unwanted cell types. Pluripotent stem cells are known to develop into all of the body’s cells and tissues.
Now, for the first time, scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine have engineered a human pluripotent stem cell line containing two ‘suicide genes’ that induce cell death in all but the desired insulin-producing cells. This double fail-safe approach, published online ahead of the March 5 issue of Stem Cell Reports, addresses the limitations of PSC-derived beta cells and opens the door to creating safe cell-replacement therapies for people living with T1D.
Looming Clinical Trials Warrant Safeguards
With clinical trials already initiated using PSC-derived beta cell progenitors and newer approaches with functional beta-like cells on the horizon, the need to ensure patient safety is of paramount importance. Research has shown that only about 30 – 40 percent of beta-like cells are obtained through current PSC differentiation (development) protocols, leaving a significant percentage of undefined cells in the balance. Most importantly, non-differentiated cells – cells that have not yet developed into a specific type – may produce tumors upon transplantation, despite recent protocol refinements.
To address these concerns, the DRI team set out to engineer pluripotent stem cell lines that selectively destroy both tumorigenic cells and cells that do not produce insulin, like liver, brain, muscle cells and others. The team tested their approach both in vitro and in vivo in a mouse model of diabetes that mimics the disease condition in humans. Their results demonstrated the removal of all unwanted cells.
“Not only did our strategy prevent the formation of tumors, but also eliminated them completely when we switched on the suicide genes only after the tumors were fully grown,” said lead study author Juan Dominguez-Bendala, Ph.D., director of stem cell development for translational research and research associate professor of surgery at the Diabetes Research Institute, University of Miami Miller School of Medicine.
No other research method reported thus far offers the same degree of safety and specificity, as conventional suicide gene-based strategies bring about the destruction of the entire graft (transplant) or do not selectively expand the population of the needed cells.
While the team focused on deriving insulin-producing cells, this strategy, if clinically successful, has far-reaching applications beyond diabetes.
“By changing just one module of our suicide cassettes, we could make the strategy specific for any tissue of your choice. Our main interest is beta cells, but it could also be tailored to select for neurons, heart or liver cells, for example,” explained Dr. Dominguez-Bendala.
In type 1 diabetes, the insulin-producing islets cells of the pancreas have been mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. Islet transplantation has restored natural insulin production in people with type 1 diabetes, as DRI scientists have published, but there are not enough cells to treat the millions of patients who can benefit. Addressing the shortage of insulin-producing cells would address one of the major challenges that stand in the way of a biological cure for the disease.
Stem cells harboring a set of suicide genes have several paths ahead of them: First, they can stop dividing and become any non-beta cell of the body. For instance, muscle, blood or bone. A second alternative is to keep dividing and form a tumor (teratoma). The third option is to become insulin-producing beta cells. Thanks to the introduced genetic modification, the first two paths bring about the destruction of any cell that takes them. Only those who “choose” the right path (i.e., pancreatic beta cells) survive.
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About the Diabetes Research Institute
The Diabetes Research Institute at the University of Miami Miller School of Medicine leads the world in cure-focused research. As one of the largest and most comprehensive research centers dedicated to curing diabetes, the DRI is aggressively working to develop a biological cure by restoring natural insulin production and normalizing blood sugar levels without imposing other risks. Researchers have already shown that transplanted islet cells allow patients to live without the need for insulin therapy. Some study participants have maintained insulin independence for more than 10 years. The DRI is now building upon these promising outcomes through its BioHub strategy, a multidisciplinary, three-pronged approach for addressing the major challenges that stand in the way of a cure: eliminate the need for anti-rejection drugs, reset the immune system to block autoimmunity, and develop an unlimited supply of insulin-producing cells. For more information, please visit DiabetesResearch.org, call 800-321-3437, or Tweet @Diabetes_DRI.
The research projects that comprise this study receive philanthropic support from the Diabetes Research Institute Foundation (DRIF). Funding was also provided by JDRF (grant number 5-2006-392).
Lori Weintraub, APR