For patients with type 1 diabetes, controlling the disease can be like walking a tightrope. While existing therapeutics will continue to improve, the future of treatment lies with next-generation regenerative medicine therapies. By Melena Bellin, MD.
For the 1.6 million Americans living with type 1 diabetes (T1D), optimally controlling their disease can be like walking a tightrope. If glucose levels are too high, patients face a host of risks, including cardiovascular, nerve damage, kidney damage/failure, blindness, and amputations. On the other hand, if blood glucose levels are too tightly controlled, patients are at higher risk of severe hypoglycemia (low blood sugar) and seizures.
Managing the disease is an arduous, 24-hour process despite advances in insulin management, including hybrid closed-loop insulin pumps and continuous glucose monitoring. While improvements will continue to be made with existing therapeutic approaches, the real future promise of T1D treatment lies with next-generation regenerative medicine therapies, like beta cell replacement, ideally using a regenerable cell source such as stem cells.
Regenerative Medicine Offers Hope for Insulin Independence
T1D is an autoimmune disease that destroys the functioning of pancreatic beta cells (a type of islet cell) responsible for making insulin. Over the past decade, scientists have been researching new regenerative medicine techniques that enable replacement of these malfunctioning cells with implanted cells that have been created in the lab.
Studies have evaluated transplants with cadaver-derived pancreatic islet cells. Scientists demonstrated proof-of-concept for these transplants in terms of helping patients obtain better glycemic control, avoid severe hypoglycemia, and lessen the need for daily insulin treatments, with many even achieving freedom from insulin injections.1
Despite these successes, cadaver-derived transplants have limitations. The main one is lack of supply. Patients often must wait years before donor cells become available for transplants because very few people are eligible to donate their pancreas for islet transplant given restrictions on consent for donation from family members and prohibition on accepting donors with medical conditions such as cancer or infection. In addition, the requirement for lifelong immunosuppression and risks associated with anti-rejection medications limits the transplantation of cadaveric islets to the most high-risk adult patients with T1D.
The combined promise and limitations of cadaver-derived islet cell transplants contributed to the development of stem cell-derived therapies that can overcome supply challenges. Donor stem cells can be developed in vitro to mature into a pancreatic islet lineage, allowing for a renewable cell source. Several companies are pioneering these regenerative medicine-based, novel cell replacement therapies coupled with medical device systems that enclose cells for implantation.
One approach, led by clinical-stage regenerative medicine company ViaCyte Inc., involves the delivery of millions of pancreatic endoderm cells contained in credit-card pouches that enable vascularization, requiring concurrent immunosuppression. Promising findings from an ongoing, first-in-human, Phase 1/2 clinical trial studying this approach were presented at the June 2021 American Diabetes Association’s Virtual 81st Scientific Sessions. The data, from a T1D patient, showed clinically meaningful improvements in glycemic control with decreased need for exogenous insulin.2 In addition, two recently published papers in Cell Reports Medicine3 and Cell Stem Cell4 showed proof-of-concept for an earlier configuration of the device. In the former paper, six patients implanted with the device had positive C-peptide levels (a biomarker for insulin produced from the stem cell-derived islets) as early as six months post-implant and suggest that the implanted cells can be differentiated into a potentially scalable, renewable source of insulin-producing pancreatic islet cells. The latter paper showed similar encouraging findings in 17 patients, including 13 percent more time in target glucose range on average and some reduction in the required amount of injected insulin.
Other companies are working on different stem cell-derived approaches. Vertex Pharmaceuticals, for example, is conducting an early-stage clinical trial implanting more mature pancreatic islet cells in patients directly through the portal vein with a deviceless approach that requires immunosuppression. Meanwhile, Seraxis Technologies also has developed a stem cell line that matures into islets but has not yet been tested in the clinic. [Editor’s Note: In October 2021, Vertex announced that the first patient treated with its cell therapy needed 91% less insulin 90 days after receiving the cell infusion and saw a significant reduction in HbA1c without any severe hypoglycemic events or other safety issues, marking the first time a T1D patient has achieved robust restoration of islet cell function from such a cell therapy. The company plans to file an IND in 2022 to begin clinical studies of its encapsulated islet cell program, which may eliminate the need for immunosuppressants.]
Seeking to Eliminate Immunosuppression
Ultimately, researchers want to overcome the need to give immunosuppressants with these therapies. It may eventually be possible to lower anti-rejection drug doses or give them on a short-term basis as is done with inflammatory bowel disease or arthritis. Doing so would enable patients with T1D to lead normal lives in terms of infection risk; however, it would require development of new immunosuppression technologies, such as those that could re-train the immune system to accept implanted islets as part of the patient versus foreign.
Encapsulation devices that protect implanted cells from immune system attack are another approach; however, they must be designed to still enable oxygen to reach the delivered cells. Scientists are at various stages of developing and testing these methods.
An innovative solution to the challenges of immunosuppression is to employ gene-editing approaches. Research is underway to edit cells to avoid destruction by patients’ immune systems.ViaCyte and CRISPR Therapeutics have partnered to develop such a product and in February, announced the dosing of the first patient in a Phase I clinical trial. After gene-editing, the stem cell line will be differentiated into pancreatic endoderm cells. If the gene-editing successfully enables generation of pancreatic cells capable of evading the immune system, it would eliminate the need for chronic immune suppression. Moreover, it would have potential application in all patients with T1D as well as those with insulin-requiring type 2 diabetes.
Numerous scientists are working to optimize these approaches and advance them in the clinic.While this is a central part of the equation, as regenerative medicine therapies develop further, access will be a key consideration. Payors will need to be brought on board. Currently, human islet cell transplants are not covered by US insurance plans, but if these new treatments can free patients from insulin dependence, they will offer a significant cost savings. The T1D community is movingcloser to a functional cure than ever before.The potential impact ofnew regenerative medicine techniqueson the lives of people living with T1D is enormous. Freeing them from the crushing burden of insulin dependence will usher in profound physical and psychological relief.
Melena Bellin, MD, is Associate Professor of Pediatric Endocrinology and Diabetes and the Director of Research for Islet Autotransplantation at the University of Minnesota. She is is a site investigator for the PEC-DIRECT study for Viacyte. She declares the additional conflicts of interest: DexCom (research support), Insulet (DSMB member), ARIEL precision medicine (advisory board).
1Gamble A, Pepper AR, Bruni A, et al. The journey of islet cell transplantation and future development.Islets. 2018; 10(2):80-94.
3Shapiro et al., Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in encapsulation device. Cell Reports Medicine, December 21, 2021.https://doi.org/10.1016/j.xcrm.2021.100466
4Ramzy A, Thompson D, Ward-Hartstone K, et al. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell. doi: 1.1016/j. stem 2021. 10.003
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