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.
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.—Jay Skyler, University of Miami Miller School of Medicine
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.
ViaCyte, on the other hand, develops its ESCs into two main cell types that are only partially differentiated: multipotent pancreatic progenitors that can differentiate into various types of pancreatic cells—including not just endocrine but exocrine or ductal cells—and immature hormone-producing cells.
These less mature cell stages offer some advantages: in particular, they adapt more easily to the inflamed environment triggered by transplantation, says Kevin D’Amour, ViaCyte’s chief scientific officer. “Once you reach a certain stage in differentiation under cell culture conditions,” Hebrok elaborates, “if you then take that cell and put it into the natural environment of an animal, there is further development and maturation. There’s some magic in the animal that we don’t fully understand yet that is really supportive in providing the environment that allows these cells to turn into fully mature, fully differentiated cells. The cells know what to do and they just get there.”
Regardless of starting cell type, the companies say they are ready to churn out their cells in large numbers. Semma, for example, can make more islet cells in a month than can be isolated from donors in a year in the United States, Sanna says, and the company’s “pristine” cells should perform better than donor islets, which are battered by the aggressive techniques required for their isolation.
As these products, some of which have already entered clinical trials, move toward commercialization, regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency have expressed concern about the plasticity of the reprogrammed cells. All three firms subject their cells to rigorous safety testing to ensure that they don’t turn tumorigenic. Before successful trials, companies won’t know the dose of beta cells required for a functional cure, or how long such “cures” will last before needing to be boosted. There’ll be commercial challenges, too: while the companies are investing heavily to develop suitable industrial processes, all acknowledge that no organization has yet manufactured cell therapies in commercial volumes.
Nevertheless, there’s growing confidence throughout the field that these problems will be solved, and soon. “We have the islet cells now,” says Alice Tomei, a biomedical engineer at the University of Miami who directs DRI’s Islet Immunoengineering Laboratory.
“These stem cell companies are working really hard to try to get FDA clearance on the cells.”
Protecting stem cell therapies from the immune system
Whatever the type of cell being used, another major challenge is delivering cells to the patient in a package that guards against immune attack while keeping cells fully functional. Companies are pursuing two main strategies: microencapsulation, where cells are immobilized, individually or as small clusters, in tiny blobs of a biocompatible gel; and macroencapsulation, in which greater numbers of cells are put into a much larger, implantable device.
ViaCyte, which recently partnered with Johnson & Johnson, launched its first clinical trial in 2014. The trial involved a macroencapsulation approach that packaged up the company’s partially differentiated, ESC-derived cells into a flat device called the PEC-Encap. About the size of a Band-Aid, the device is implanted under the skin, where the body forms blood vessels around it. “It has a semipermeable membrane that allows the free flow of oxygen, nutrients, and glucose,” says ViaCyte’s chief executive officer, Paul Laikind. “And even proteins like insulin and glucagon can move back and forth across that membrane, but cells cannot.”
The device is deceptively simple but it allows us to put [in] a fully curative dose of islets.—Bastiano Sanna, Semma Therapeutics
The trial showed that the device was safe, well tolerated, and protected from the adaptive immune system—and that some cells differentiated into working islet cells. But most cells didn’t engraft effectively because a “foreign body response,” a variant of wound healing, clogged the PEC-Encap’s membrane and prevented vascularization. ViaCyte stopped the trial and partnered with W. L. Gore & Associates, the maker of Gore-Tex, to engineer a new membrane. “With this new membrane,” says Laikind, “we’re not eliminating that foreign body response, but we’re overcoming it in such a way that allows vascularization to take place.” The company expects to resume the trial in the second half of this year, provided it receives the green light from the FDA.
In 2017, ViaCyte moved ahead with a trial of a related device specifically for high-risk patients on waiting lists for donor transplants. The PEC-Direct capsule is similar to the PEC-Encap except that it features ports in the membrane to promote vascularization of the device. This approach requires that patients take immunosuppressive drugs, but fortunately the necessary regimens have become easier and safer in recent years, Laikind says. The device is now being tested in additional high-risk patients. If all continues to go well, ViaCyte will apply for FDA approval.
Semma is also developing macroencapsulation methods, including a very thin device that in prototype form is about the size of a silver dollar coin. The device is “deceptively simple but it allows us to put [in] a fully curative dose of islets,” Sanna says. “It protects the cells from the immune system with a particular type of membrane that keeps the immune system out, allowing for very fast and precise exchange of glucose and insulin in the body.” The company expects to launch a clinical trial of the device in early 2021.
Semma is also investigating microencapsulation alternatives. At the same time, the company is advancing toward clinical trials using established transplantation techniques to administer donated cadaver cells to high-risk patients who find it particularly difficult to control their blood glucose levels. These cells are infused via the portal vein into the liver, and patients take immunosuppressive drugs to prevent rejection.
Sigilon is working on its own microencapsulation technology. Launched in 2016 on the back of work by the labs of Robert Langer and Daniel Anderson at MIT, the company has created 1.5-millimeter gel-based spheres that can hold between 5,000 and 30,000 cells (Nat Med, 22:306–11, 2016). Each sphere is like a balloon, with the outside chemically modified to provide immunoprotection, says Sigilon chief executive officer Rogerio Vivaldi. “The inside of the balloon is full of a gel that creates almost a kind of a matrix net where the cells reside.”
In 2018, shortly after partnering with Eli Lilly, Sigilon and collaborators published research showing that islet cells that were encapsulated in gel spheres and transplanted into macaques remained functional for four months (Nat Biomed Eng, 2:791–92). The company hasn’t disclosed a time frame for a type 1 diabetes trial “but we’re moving pretty quickly,” says chief scientific officer David Moller.
Eventually, all three firms hope to extend their work to treat some of the 400 million people worldwide with type 2 diabetes, many of whom eventually benefit from insulin injections. The recent endorsements from big pharma underline the real progress in beta-cell transplants, says Aaron Kowalski, a molecular geneticist and chief executive officer at JDRF, a foundation based in New York that has funded research at ViaCyte and academic labs whose work has been tapped by Semma and Sigilon. “These companies all realize that if they don’t do it, somebody else will. It’s hard to predict exactly when, but somebody is going to make this work.”
Eric Bender is a freelance science writer in Newton, Massachusetts.