Cell replacement therapy holds promise for precision control in diabetes
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The discovery of injectable insulin has saved countless lives over the past 100 years, but the next chapter in diabetes therapies — cell replacement therapy driven by stem cell islet products — represents a momentous turning point toward a disease-modifying cure.
The global burden of diabetes and its complications presents an increasingly inexorable challenge to health care systems. The costs are staggering: More than 460 million people worldwide live with diabetes, at an annual global cost in excess of $1.3 trillion. A diabetes-related death occurs every 6 seconds, and although injected insulin has been around for 100 years and prevents acute death, it is not curative.
Although advancements in insulin formulations and wearable technologies in the form of insulin pumps and glucose monitoring devices have significantly improved patients’ quality of life and lessened the risk for incapacitating hypoglycemia, these solutions remain imprecise, still failing to restore normal physiologic control of blood glucose. Of the 1.6 million people living with type 1 diabetes in the United States, fewer than one-third are able to regulate and maintain targets for blood glucose on a consistent basis. A panoply of drugs initially developed for patients with type 2 diabetes are increasingly being used for all types of the disease. Still, a cure has yet to be found.
Islet transplantation shows proof of concept
Accrued experience with transplantation of insulin-producing islet cells over the past quarter century has provided important proof of concept that cell replacement therapy effectively stabilizes glycemic control and provides periods of complete insulin independence. Such an approach can transform the lives of patients with a tendency for hypoglycemia. Absence of severe hypoglycemia has been maintained in approximately 90% of islet transplant recipients up to 5 years after transplant.
Human islets are prepared from the pancreas organs of brain-dead organ donors and infused without surgery via the portal vein into the liver. There, the islets revascularize and release precision-controlled insulin.
Drawbacks remain, however, most notably a need for lifelong immune suppression that carries risks for nephrotoxicity, infection and cancer. When transplants are carried out in people with type 1 diabetes, preventing recurrent autoimmune islet destruction remains a challenge with some patients.
Cell replacement therapy will likely be highly effective in insulin-requiring type 2 diabetes but has yet to be tested. Furthermore, if this method were to become mainstream therapy, reliance on a scarce organ donor pool of fewer than 40,000 donors worldwide per year will never match the need. Therefore, new methods to manufacture potentially limitless islets from stem cells have come to the forefront of translational research.
Stem cells allow mass production
Human stem cell-derived islets, capable of secreting regulated insulin at physiologic levels, may now be generated from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). The advantage of hESC islets is that these can readily be mass produced at scale; however, they remain allogeneic to the transplant recipient. In this case, either immunosuppression must be given, or the cells must be shielded in some way by a macroencapsulation device or through CRISPR-Cas9 gene editing.
Alternatively, iPSC islets are autologous to the recipient and do not require immunosuppression; however, they are far more complex and costly to produce. In both cases, preventing recurrent autoimmune destruction of transplanted cells will remain important in the subgroup of patients with type 1 diabetes.
The process for directed differentiation of hESCs or iPSCs from their undifferentiated state to creation of polyhormonal, insulin-secreting islets artificially recapitulates normal pancreatic embryologic development by adding sequential small molecule growth factors during a 27-day process in a culture dish. Reliable methods for achieving this first were described by D’Amour and colleagues at Cythera Inc. (now ViaCyte Inc.) with creation of a highly potent CyT49 cell line. These methods have been further advanced by this team and others to produce cells that match the characteristics of human islets, that differentiate and mature in vivo and are capable of regulating normal human set levels of glucose.
New products address delivery challenges
ViaCyte’s PEC-01 GMP product derived from its CyT49 line has been tested in patients by transplanting cells contained within small, flat macroencapsulation polymer devices beneath the skin. These cells have been tolerated remarkably well by patients. One subject in its PEC-Direct trial (microperforations to improve local neovascularization and oxygen delivery) achieved measurable C-peptide of 0.8 ng/mL coupled with improved glycemic control (88% glycemic time in range) and reduction in HbA1c from 7.4% to 6.6% at 39 weeks. Furthermore, almost one-third of patients in one cohort of this study had detectable C-peptide at varying timepoints, suggesting promise of this approach. The macroencapsulation device technologies and subcutaneous implantation sites remain a challenge that will need further refinement if complete restoration of endogenous insulin reserve is to be attained.
Other companies have begun researching these promising approaches, as well. Vertex Pharmaceuticals launched a phase 1/2 clinical trial in 2021 with its VX-880 hESC-derived islet product and immunosuppression, through intraportal cell delivery. Seraxis has developed an SR1423 stem cell islet product that will also shortly undergo pilot clinical testing, likely in a subcutaneous device.
Ongoing research includes efforts to make stem cell islets silent to immune attack. One approach, involving both gene deletions and additions to protect cells, is expected to be tested in clinical trials in the coming months. If cells can be transplanted successfully without the need for immune suppression, researchers may well be on the way toward paving a path for a potential functional cure for children and adults with diabetes.
Based on the current pace of progress, major advances in diabetes therapies certainly will not take another 100 years.
References:
- Agulnick AD, et al. Stem Cells Transl Med. 2015;doi: 10.5966/sctm.2015-0079.
- Bruin JE, et al. Diabetologia. 2013;doi:10.1007/s00125-013-2955-4.
- CITR Coordinating Center. Collaborative Islet Transplant Registry 10th Annual Report. Rockville, MD. Available at: https://citregistry.org/system/files/10th_AR.pdf. Published Jan. 6, 2017. Accessed Dec. 6, 2021.
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- Juvenile Diabetes Research Foundation (JDRF) Diabetes Facts. 2021. Available at: https://www.jdrf.org/t1d-resources/about/facts/. Accessed Dec. 6, 2021.
- JDRF: Vertex has a new horizon: Curing type 1 diabetes. Available at: https://www.jdrf.org/blog/2021/02/01/vertex-new-horizon-curing-type-1-diabetes/. Published Feb. 1, 2021. Accessed Dec. 6, 2021.
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- Seraxis announced closing of $40M Series C Financing Round. Available at: https://www.prnewswire.com/news-releases/seraxis-announced-closing-of-40m-series-c-financing-round-301224232.html. Published Feb. 9, 2021. Accessed Dec. 6, 2021.
- Shapiro AM, et al. Nat Rev Endocrinol. 2017;doi:10.1038/nrendo.2016.178.
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For more information:
A.M. James Shapiro, MD, PhD, FRCS(C), MSM, FRSC, is director of the Clinical Islet Transplant Program at the University of Alberta, Canada. He can be reached at jshapiro@ualberta.ca.
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