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Universal donor stem cells may hold answer to beta-cell transplantation barriers

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NEW ORLEANS — Biologically modified human pluripotent stem cells used to create mature, insulin-producing beta-cells may offer a breakthrough solution to a problem that has frustrated diabetes researchers for decades, according to a speaker at the American Diabetes Association Scientific Sessions.

Functional beta-cells, made with embryonic stem cells or induced pluripotent stem cells, can already be made on a large enough scale that they are ready for transplantation, said Chad A. Cowan, PhD, an associate professor in the department of stem cell and regenerative biology at Harvard University and director of the diabetes program at the Harvard Stem Cell Institute.

Chad A. Cowan

The final hurdle, he said, is to protect the beta-cells that would be transplanted into humans from an attack by the body’s own immune system.

“The challenge, though, is just that — transplantation,” Cowan said during a press conference. “If I give the [beta]-cells back to the type 1 diabetic, they have an autoimmune disease. Their immune system is trained to kill those cells. So, [the immune system will] just kill them again.”

Potential solutions currently being tested include creating physical barriers to protect the transplanted cells, such as retrievable devices or using nonretrievable, encapsulated cells, Cowan said. The Harvard Stem Cell Institute recently collaborated with the David H. Koch Institute for Integrative Cancer Research at MIT and other institutions to develop an implantable device that will shield the beta-cells from attacks for several months in mouse models.

ViaCyte is also conducting a clinical trial, STEP ONE, using pancreatic progenitor cells and an encapsulation delivery system designed to protect the cells from a patient’s immune system.

A novel solution, Cowan said, would involve biologically modifying the cells to be protected from the immune system during an autoimmune attack.

“That’s the universal donor stem cell,” Cowan said. “The idea was to create an off-the-shelf, quality-controlled product that is compatible with any given patient, and can be produced in large quantities that any pluripotent stem cell can be made in.”

Universal donor stem cells offer multiple advantages in that they can be stored, distributed and be made readily available to any patient in need.

“This can be incredibly well controlled,” Cowan said. “This single [cell] line, you can know everything about it: how well it differentiates, all the genetic background behind it, whether it has any infectious agents, on and on. It’s a single solution to a very large problem.”

The strategy to modify the cells is two-pronged, Cowan said. Researchers aim to reduce immunogenicity by removing the MHC molecules on the surface of the cells that “talk” to the immune system, while also inducing tolerance in those cells, using clues gleaned from both pregnancy and immuno-oncology cancer research.

“There are specialized forms of immune-regulatory molecules that express right at the fetal-maternal interface that seem to tell the immune system in the uterus not to reject that developing fetus,” Cowan said. “We want to put those molecules into the cells, so that the cells are also capable of telling the immune system the same thing: Don’t reject us.”

The universal donor research unlocks the potential of cell-replacement therapy, Cowan said. Induced pluripotent stem cells were a “great first step,” but it is not feasible to make GMP-quality beta-cells for all the patients who would need them, he said.

“The solution needs to be some type of allogeneic transplant for you to do that,” Cowan said during his presentation. “I think this type of universal stem cell can unlock that regenerative capacity for diseases.” – by Regina Schaffer

Reference:

Cowan CA. Universal Donor Stem Cells: Removing the Immune Barrier to Transplantation using Gene Editing. Presented at: American Diabetes Association 76th Scientific Sessions; June 10-14, 2016; New Orleans.

Disclosure: Cowan reports he is a co-founder of CRISPR Therapeutics..