Paving the Road to Cure Type 1 Diabetes

February 16, 2023

Paving the Road to Cure Type 1 Diabetes: Immunotherapy, Regenerative Medicine, Bioengineering, and Vaccines

Type 1 diabetes mellitus (T1DM) is thought to arise from an autoimmune attack destroying pancreatic β-cells. The pancreatic beta cells are endocrine cells that synthesize, store, and release insulin. Currently, the general treatment for T1DM is close monitoring of daily blood glucose levels with injections of long-acting insulin (e.g., Lantus, Levemir) and short-acting/mealtime insulin (e.g., Humalog, Novolog). Patients typically continue these treatments indefinitely after onset. 

What if there was a way to restore the pancreatic β-cells back to optimal health and function? Cutting-edge research is being done in the fields of immunotherapy, regenerative medicine, bioengineering and a possible vaccine which could pave the way to a durable cure for T1DM.

Immunotherapy

Immunotherapies are treatments that reprogram the immune system so that it no longer attacks and destroys insulin-producing cells in the pancreas. In the future, they could stop type 1 diabetes progression or prevent the condition entirely.  In 2022 The US Food and Drugs Administration (FDA) approved the world’s first ever immunotherapy for type 1 diabetes, teplizumab, also called Tzield (1). TZIELD is an antibody which binds to certain immune system cells and is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D (1). TZIELD is administered by intravenous infusion. Tzield may deactivate the immune cells that attack insulin-producing cells, while increasing the proportion of cells that help moderate the immune response (2). 

Regenerative Medicine

One aspect of regenerative medicine involves the use of stem cells. Stem cells are precursors of normal adult tissues that can evolve to become mature tissues like bone, muscle and cartilage. While embryonic stem cells remain a controversial area of science and medicine, stem cells can also be found and extracted from adult tissues like bone marrow and fat. Stem cells have been used to generate insulin-producing β-cells (3). In an important 2014 study, human stem cells were transplanted into immunodeficient mice, and demonstrated successful signs of curing diabetes in these mice (4). 

Pancreatic islet cells can also be obtained from cadaveric donors and then transplanted into T1DM patients. In a small University of Chicago study of nine diabetic patients who received islet transplantation, four of nine patients stayed insulin-free over the course of 5 years (the other 5 subjects dropped out). Over those 5 years patients received three islet infusions (5). A lack of availability of human islet donors has led scientists to try to expand islet cells in vitro. Pig islets are another potential source; however, there is the challenge of immune rejection as well as potential for infection from retroviruses contained in the pig cells. 

What if we could protect the transplanted cells from attack by the immune system? 

Bioengineering

This is where the field of Bioengineering comes in. Scientists are exploring the use of a semi-permeable membrane to protect transplanted cells from the immune system. Think of this like a shield around the newly implanted cells. Biomaterials that allow the normal flow of nutrients/waste, oxygen, and insulin but prevent attack from the immune system. Among the possible materials, sodium alginate, a polysaccharide derived from algae, is often used as the protective barrier to encase islets while allowing nutrient and waste exchange (6). Other possible solutions are medical devices like the one developed by the company Viacyte. Encaptra is a thin membrane that is intended to protect transplanted β-cells from interacting with the body’s own immune cells. The device contains pancreatic progenitor cells (similar to stem cells). The expectation is that cells will more fully mature into human pancreatic cells (including β-cells) that can respond to a patient’s post-prandial high glucose levels in the blood. This trial is currently active (7).

Vaccines

This approach is actually considered an ‘inverse vaccine’ because it reverses certain immune responses, rather than activating them. “It engages the immune system and causes desensitization, like allergy treatments…The goal is to stop the immune attack on the insulin-producing cells and stop the disease progression” said Bart O. Roep Ph.D., who led the research team investigating this vaccine. The team took a patient’s immune cells and manipulated them in a laboratory to become anti-inflammatory. They then loaded the cells with a fragment of insulin-producing beta cells from the pancreatic islets and added vitamin D3. They then injected the modified immune cells back into the participants. The vaccine was reported to be safe based on the results from a small Phase I trial in the Netherlands. The vaccine is currently in a Phase 1 clinical trial for the first time in the United States (8, 9). 

Paving the way

This research is particularly promising as it shows a shift away from simply treating symptoms to curing and possibly preventing the root cause of illness. While the research is very exciting, there is still a long way to go in terms of safety, efficacy, and large-scale feasibility. The most important issues for treatment of T1DM are ensuring improved quality of life for the patients and that treatments are affordable and effective for long periods of time.

1. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes

2. Tzeild manufacturer package insert 

3. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A (2009) 106:15768–73. doi:10.1073/pnas.0906894106

4. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med (2000) 343:230–8. doi:10.1056/NEJM200007273430401

5. Tekin Z, Garfinkel MR, Chon WJ, Schenck L, Golab K, Savari O, et al. Outcomes of pancreatic islet allotransplantation using the Edmonton protocol at the University of Chicago. Transplant Direct (2016) 2:e105. doi:10.1097/TXD.0000000000000609

6. Buder B, Alexander M, Krishnan R, Chapman DW, Lakey JR. Encapsulated islet transplantation: strategies and clinical trials. Immune Netw (2013) 13:235–9. doi:10.4110/in.2013.13.6.235

7. https://viacyte.com/pipeline/ 

8. Tatjana Nikolic, Jaap J Zwaginga, Bas S Uitbeijerse, Nicky J Woittiez, Eelco J de Koning, Henk-Jan Aanstootet al. Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—for type 1 diabetes. Published:May 05, 2020 DOI:https://doi.org/10.1016/S2213-8587(20)30104-2

9. https://clinicaltrials.gov/ct2/show/NCT04590872?term=NCT04590872&draw=2&rank=1