Each year, 40,000 people in the United States are diagnosed with type 1 diabetes, an autoimmune disease that wipes out insulin-producing pancreatic beta cells and raises blood glucose to dangerously high levels.
Patients deal with the condition by self-administering insulin and managing their blood glucose levels around the clock—no easy feat, even for those who are aided by insulin pumps and continuous glucose monitors that help determine insulin dosage.
A small number of patients who find it particularly difficult to control their blood glucose levels are treated successfully by beta-cell transplants from cadaver donors. But the supply of these cells is tiny, and patients have to take immunosuppressive drugs to tolerate the transplanted cells.
In recent years, advances in the lab have drawn attention to an alternative approach. Perhaps most dramatically, in 2014, a research group at Harvard University reported using insulin-producing cells derived from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to lower blood glucose levels in mice (Cell, 159:P428–39). Spurred by such successes, numerous labs now are exploiting rapid progress in human stem cell technology to develop functional equivalents of beta cells and the other pancreatic cell types. Other groups are developing novel biomaterials to encapsulate such cells and protect them against the immune system without the need for immunosuppressants.
Given progress on both of these fronts, “there has been a sea change” in how the biomedical industry views beta-cell transplants, says cell biologist Matthias Hebrok, who researches diabetes at the University of California, San Francisco. Perhaps most notably, major pharmaceutical companies and life sciences venture capital firms have invested more than $100 million in each of the three most prominent biotechs hoping to bring such treatments into clinical use: Cambridge, Massachusetts–based companies Semma Therapeutics and Sigilon Therapeutics, and ViaCyte of San Diego.
“I’m glad to see that industry is becoming involved, because that will give the push to move forward the ability to do beta-cell replacement and do it on a wide scale,” says Jay Skyler, an endocrinologist at the University of Miami Miller School of Medicine and deputy director of clinical research and academic programs at the school’s Diabetes Research Institute (DRI). “I think the whole field is about to really explode.”
Making insulin-producing cells from stem cells
Basic research keeps elucidating new aspects of beta cells—for instance, there seem to be several subtypes—so the gold standard for duplicating the cells is not entirely clear. Today, however, there is “a handful of groups in the world that can generate a cell that looks like a beta cell,” says Hebrok, who currently acts as scientific advisor to Semma and Sigilon, and has previously advised ViaCyte. “Certainly, companies have convinced themselves that what they have achieved is good enough to go into patients.”
The stem cell reprogramming methods that the three companies use to prompt cell differentiation in fact create a mixture of islet cells. Beta cells sit in pancreatic islets of Langerhans alongside other types of endocrine cells. Alpha cells, for example, churn out glucagon, a hormone that stimulates the conversion of glycogen into glucose in the liver and raises blood sugar. Incorporating a mixture of these cell types is probably not a bad thing for transplants, says Olivia Kelly, Sigilon’s head of islet cell therapy research. “We definitely want a high proportion of beta cells, but at the end of the day, we might want to mimic the natural composition of the mature islet, with the cells all talking to each other.”
Although the companies agree on the positive potential of islet cell mixtures, they take different approaches to developing and differentiating their cells. Sigilon and Semma focus on developing beta cells from iPSCs, while ViaCyte instead starts with ESCs. The companies also differ in the level of differentiation they achieve before implant.
Semma, which was launched in 2014 to commercialize the Harvard group’s work and counts Novartis among its backers, describes its cells as fully mature, meaning that they are completely differentiated into beta or other cells before transplantation. “Our cells are virtually indistinguishable from the ones you would isolate from donors,” says Semma chief executive officer Bastiano Sanna.
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