Researchers at the University of Missouri (MU), Georgia Institute of Technology, and Harvard University have developed a transplantation therapy for type 1 diabetes (T1D) that involves transplanting insulin-producing pancreatic islets from a donor into a recipient, but without the need for lifelong immunosuppression. The technology uses a novel biomaterial that contains a novel protein called SA-FasL, which promotes immune tolerance, tethered to the surface of microgel beads. When mixed with pancreatic islets, this biomaterial supports islet cell survival after transplantation, so that the recipient doesn’t then have to take immunosuppressive drugs for the long term to prevent rejection.
In a preclinical study conducted at Massachusetts General Hospital (MGH), the researchers successfully tested the biomaterial in a nonhuman primate model of T1D. Their results confirmed robust control of glucose and graft survival in animals receiving transplants of the islet-containing biogel, for more than six months. When the researchers removed the grafts the animals’ blood sugar levels were again elevated.
“Our strategy to create a local immune-privileged environment allowed islets to survive without long-term immunosuppression and achieved robust blood glucose control in all diabetic nonhuman primates during a six-month study period,” said lead author Ji Lei, MD, an associate immunologist at MGH and an assistant professor of surgery at Harvard Medical School. “We believe that our approach allows the transplants to survive and control diabetes for much longer than six months without antirejection drugs because surgical removal of the transplanted tissue at the end of the study resulted in all animals promptly returning to a diabetic state.” The research team is now planning a clinical trial.
Lei and colleagues reported on their technology and preclinical trial in Science Advances, in a paper titled, “FasL microgels induce immune acceptance of islet allografts in nonhuman primates.”
T1D results from autoimmune destruction of the pancreatic islet ß cells, the authors explained. “The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections,” said Haval Shirwan, MD, PhD, a professor of child health and molecular microbiology and immunology at the MU School of Medicine, and one of the study’s lead authors. “Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is eliminated, the immune system’s command-and-control mechanism kicks in to eliminate any rogue cells. However, if this mechanism fails, diseases such as type 1 diabetes can manifest.”
Diabetes affects the body’s ability to produce or use the hormone insulin, which normally helps to regulate how blood sugar is used in the body. People with T1D do not make insulin, and therefore are unable to control their blood sugar levels. That loss of control can also lead to life-threatening complications such as heart disease, kidney damage, and eye damage.
Lifelong daily insulin treatments are standard for T1D patients, and so transplantation therapy with pancreatic islets that could replace lost ß cell represents an attractive option. However, this strategy requires that patients take lifelong immunosuppressive drugs to prevent rejection. “Those immunosuppressive regimens are toxic to the patient, so a major goal in the field has been to develop approaches that will allow you to put in this graft and get it to function without chronic immunosuppression,” said Georgia Institute of Technology co-research lead Andrés García, PhD, who is the Petit Chair in Bioengineering and Regents’ Professor in the George W. Woodruff School of Mechanical Engineering and executive director of the Petit Institute for Bioengineering and Bioscience.
Over the last two decades, Shirwan and Esma Yolcu, MD, PhD, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys “rogue” immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the surface of the islets. “A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die,” said Yolcu. “… our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells.”
The researchers had previously tested the approach in diabetic mice. “We previously demonstrated that cotransplantation of SAFasL–presenting microgels with allogeneic islets under a transient cover of rapamycin resulted in indefinite graft survival in mice,” they wrote.
García, added, “Immunosuppression is a significant problem for patients, but in our prior work we showed that this biomaterial, this microgel, is a potent immunomodulatory molecule, and can induce permanent acceptance of the new cells. But that study was done in mice, and the immune system of a mouse is very different from a human’s. And in the progression toward clinical use, you really need to test this strategy in a large animal model.
For their newly reported study, the researchers transplanted the material in a nonhuman primate (NHP) model of diabetes. For these experiments, the microgels were transplanted to a pouch formed by the omentum—a fold of fatty tissue that hangs from the stomach and covers the intestines. “Here, we investigated the immunomodulatory potential of the SA-FasL microgel technology in a preclinical streptozotocin (STZ)–induced diabetes NHP model in which allogeneic islets and SA-FasL microgels are cotransplanted to the omental pouch,” they further explained. After transplantation, the recipient animals were treated using a single anti-rejection drug (rapamycin) for three months.
The results showed that the SA-FasL–presenting microgels cotransplanted with allogeneic islets effectively sustained long-term (>6 months) survival and “excellent glycemic control” in diabetic NHPs, without chronic immunosuppression, the authors confirmed. “These subjects demonstrated glucose-responsive insulin secretion and C-peptide levels comparable to the prediabetic state,” they wrote. “In marked contrast, control animals cotransplanted with microgels without SA-FasL rejected the islet graft acutely.” Yolcu further commented, “Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.”
The new approach could negate the need for recipients to undergo lifelong therapy using immunosuppressive drugs that counteract the immune system’s ability to seek and destroy foreign objects such as organs or cell transplants that are introduced into the body. “The major problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as high instances of developing cancer,” Shirwan said. “So, using our technology, we found a way that we can modulate or train the immune system to accept, and not reject, these transplanted cells.”
Because the biomaterial can be created in a lab and shipped anywhere, the new therapeutic is essentially off-the-shelf. And with the strategy now having been shown to work in nonhuman primates, García and his collaborators are confident that patients with type 1 diabetes could have a powerful new treatment option. García is co-founder of the company that licensed the technology, iTolerance, which is already discussing plans for human clinical trials with the U.S. Food and Drug Administration.
“We are pretty pumped – this is very exciting, and these are hopeful results for people fighting type 1 diabetes,” said García, corresponding author and part of a 20-person research team. “This work wouldn’t have been possible with this team science approach.”
To develop the commercial product, the MU researchers collaborated with García and the team at Georgia Tech to attach FasL to the surface of microgels, for the proof-of-efficacy study in a small animal model. Then, they joined with Lei, and with co-corresponding author James F. Markmann, MD, PhD, chief of the Division of Transplant Surgery and director of Clinical Operations at the Transplant Center at MGH, to assess efficacy of the FasL-microgel technology in a large animal model.
Lei, who is also director of the human islet/cell processing special service cGMP facility at MGH, noted that transplanting islets to the omentum has several advantages over the current clinical approach of transplanting to the liver. “Unlike the liver, the omentum is a nonvital organ allowing its removal should undesired complications be encountered,” he explained. “Thus, the omentum is a safer location for transplants to treat diabetes and may be particularly well suited for stem cell-derived beta cells and bioengineered cells.”
Markmann further pointed out that the nonhuman primate study is a highly relevant preclinical animal model. “This localized immunomodulatory strategy succeeded without long-term immunosuppression and shows great potential for application to type 1 diabetes patients,” he said.
The authors noted that their approach for local delivery of FasL with the graft also has advantages over potential gene therapy approaches. “Our strategy is to deliver FasL locally within the graft microenvironment in a controlled and sustained fashion using advanced synthetic materials,” they noted. “This is a unique advantage over FasL gene therapy, because uncontrolled, continuous expression of FasL, which has pleiotropic activity and various modes of expression that may be differentially regulated by target tissues, may have unintended consequences.” Moreover, they noted, “SA-FasL–engineered microgels provide the flexibility of an off-the-shelf product for wider clinical applications, as these immunomodulatory materials can be prepared at the time of transplantation and simply admixed with islets for delivery without the need of encapsulating or chemically modifying islets to present proteins.”