Description of Project
A cure for T1D will require both a replenishable source of β cells and strategies for promoting those β cells’ survival and function despite stressors they will face when implanted into a recipient with T1D: chiefly both autoimmune and alloimmune reactions, but also challenges from metabolic stress and possibly infectious insults. The challenge of generating insulin producing β cells has now been solved, as demonstrated by the implantation of stem cell derived islets (SC-islets) into an individual with long standing T1D who was then able to achieve normal blood glucose control without injecting insulin (results announced at the June 2021 ADA Annual Session)- though the recipient has required general immunosuppression with its known toxicity. The next step is to find strategies to protect the transplanted SC-islets without the need for toxic immunosuppression.
Others are pursuing encapsulation with various micro devices to isolate the transplanted SC-islets from immune attack1-3, attempting to overcome well recognized limitations of such strategies4. The JDRF New England Center of Excellence (NE COE) goal is to transplant unencapsulated SC-islets genetically modified so as to evade anticipated stressors expected when implanted into a human with T1D, and without toxic immunosuppression.
Advantages of the unencapsulated genetically modified SC-islet approach include that the implanted cells: (1) have direct contact with a natural blood supply since islets are known to require a rich capillary network to function normally5,6, and (2) are more easily transplanted if subsequent doses are required. Moreover, recent studies have suggested that strategies focused on improving β cell “heartiness” may improve their survival and function with mechanisms distinct from well-studied immunologic ones. For instance, drugs designed to prevent the expression and function of a protein called thioredoxin interacting protein (TXNIP) have been reported to improve blood glucose control in both animal models, and in humans with T1D7-9. Others are studying another metabolic pathway, the polyamine pathway 10 and its role in diabetes. Further, while still controversial, studies of T1D incidence during the COVID pandemic have suggest a potential role for that infectious agent (and others) to promote T1D onset11-13. The point is that the our insight into the mechanisms underlying T1D has evolved to a far more nuanced understanding of a complex interplay between the β cell, the general metabolic and inflammatory environment, and the immune system. With that knowledge, we aim to find genes that we can inactivate, and other gene products we can promote, all with the goal of genetically modifying SC-islets for therapeutic use.
The central premise underlying JDRF NE COE efforts is that SC-islets can be genetically modified such that they retain function when implanted into individuals with T1D. Potential SC-islet genetic modifications could include (alone or in combination) those that
• Cloak the SC-islets to make them immunologically invisible,
• Signal to infiltrating immune cells a “don’t kill me’ message
• Alter the SC-islets’ molecular machinery to increase their resilience to metabolic, infectious, inflammatory, or immunologic insults
With over 20,000 genes in the human genome, the challenge is to identify the potential “needle or needles in the haystack” that would create such curative genetically modified SC-islets.
JDRF NE COE investigators have tackled the challenge using a four-pronged approach.
1. Use mice to identify candidate genes to inactivate in human SC-islets.
2. Characterize the human immune response directed against native and genetically modified human SC-islets so that we might identify genes to express to improve the cells’ viability and function despite the immune insult
3. Exercise a robust “foundry” for human stem cell => SC-islet production.
4. Validate pre-clinical systems for assessing SC-islet function and survival.