Swapping in stem cells for diabetes treatment

With just under 50% of type 1 diabetes patients using wearable blood glucose monitors¹, medical devices are certainly having their moment. But what about treatments that can actually cure the disease?

Type 1 diabetes (T1D) and its treatments have come a long way in the last century, from what was initially a terminal illness, to one that can now be managed through insulin injections and a whole host of gadgets that monitor blood glucose levels. In T1D patients, their T cells destroy the insulin-producing β cells within the pancreas, through an autoimmune reaction. The pathology of the disease seems relatively straightforward… one might even consider it an ideal application for stem cell therapy. However, the patient’s immune system will continue to recognise and destroy β cells, no matter whether they are the patient’s own, or if they are stem cell- or donor-derived. Despite breakthroughs in the early 2000s, where insulin independence was achieved for the first time using a β cell transplant administered in conjunction with a substantial regimen of immunosuppressive drugs², scientists have struggled to find an effective solution to the problem of autoimmunity.

Haematopoietic stem cell (HSC) transplantation – replacing the immune cells

Over the years, a number of studies have investigated the use of autologous HSC transplants in attempts to reset the immune system in various autoimmune diseases including multiple sclerosis, Crohn’s disease, and T1D. This therapy hits the root cause of the disease: the autoreactive immune cells are destroyed and then replaced with new immune cells derived from stem cells. However, a large proportion of patients in these studies do not achieve insulin independence, and of those that do, a subset experience relapse around 4-6 years after receiving the therapy. This problem is inherent to autologous HSC transplants, as the same HSCs that gave rise to the autoreactive immune cells that caused the disease in the first place are used to repopulate the immune system.

Allogeneic HSC transplants, using cells from donors, have curative potential in T1D without the risk of relapse, as the HSCs are genetically different. However, the treatment is unpredictable, as patients often newly develop T1D after an allogeneic HSC transplant for the treatment of a separate condition³. More research and extensive donor matching are required to make this therapy a reality for T1D.

Stem cell-derived islet cell therapy – replacing the pancreatic cells

An alternative approach which has shown promise in recent years is the use of stem cells to replace the β cells themselves. This therapy could also be autologous or allogeneic, however most products in development are allogeneic, due to the advantages provided in the scaling up of cell products. Differentiation of stem cells into β cells in a lab that can be transplanted into humans – something we haven’t yet achieved for HSCs - was a major milestone in itself⁴. Now, research groups are experimenting by administering β cells at different stages of development, either fully differentiated or as progenitor cells at an earlier stage of development that are more robust. With all these approaches there is one constant: the need to protect the cell therapy from the patient’s immune system.

Hiding the cell therapy from the patient’s immune system

Allogeneic stem cell-derived β cells take a double hit from the immune system, as not only will the immune system recognise β cell-specific antigens, but the cell product will also be recognised as ‘non-self’. The pharmaceutical industry is rising to this challenge with a number of innovative solutions, which are being tested in clinical trials currently. Vertex pharmaceuticals recently published initial results for their stem cell therapy VX-880, showing that insulin independence was achieved in the two patients followed up for one year after receiving the therapy. Vertex have FDA clearance for a phase 1/2 clinical trial for their second generation product VX-264, which contains the same stem cell product encapsulated in a proprietary immunoprotective device. Also in development is a genetically modified cell product, comprising the same stem-cell derived β cells, edited to be hypoimmunogenic.

In July 2022, Vertex bought out their main competitor ViaCyte, who were also developing stem cell therapies for T1D, and methods to protect them from the immune system. ViaCyte had partnered with the materials powerhouse Gore (behind your lovely Gore-tex walking boots) to develop an encapsulation device for protecting their stem cell-derived β cells. They have also partnered with CRISPR to develop gene edited, hypoimmune β cells that can be used with the encapsulation devices to enhance immune evasion. We are still waiting on clinical trial results, but Vertex hope that having all the technology under one roof will get them one step closer to that evasive cure.

Future perspectives

While we may not have quite reached a cure for T1D, for some patients these therapies show much better control of blood glucose than insulin injections. It remains to be seen how durable the insulin independence is, and the exact proportion of patients that these therapies will be successful for (larger trials will be required). However, even if insulin requirements are merely reduced, this can still greatly reduce the burden of monitoring and injecting for T1D patients, improving quality of life. Beyond the stem cell field, CAR-T_reg cell therapy and AAV gene therapy to deliver genes required for insulin production to the pancreas are also being explored for their curative potential in T1D. Hopefully all this innovation will make a cure for the disease a reality for patients, that sees them binning their needles and monitors once and for all.

References

1. DeSalvo DJ, Noor N, Xie C, et al. Patient Demographics and Clinical Outcomes Among Type 1 Diabetes Patients Using Continuous Glucose Monitors: Data From T1D Exchange Real-World Observational Study. J Diabetes Sci Technol. 2023;17(2):322-328. doi:10.1177/19322968211049783

2. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230-238. doi:10.1056/NEJM200007273430401

3. Dalla Via V, Halter JP, Gerull S, et al. New-onset Post-transplant Diabetes and Therapy in Long-term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation. In Vivo. 2020;34(6):3545-3549. doi:10.21873/invivo.12197

4. Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159(2):428-439. doi:10.1016/j.cell.2014.09.040