Description of Project
The Breakthrough T1D New England Center of Excellence (NE COE) is pursuing research to prevent future cases of
Type 1 Diabetes (T1D) and to cure those already living with the disease. For those with T1D, our approach is to
transplant cells that make insulin. Such transplanted cells must produce insulin in the right amount at the right
time, allowing for normal blood glucose levels without the individual needing to constantly monitor or to inject
insulin.
Recent research has shown that transplanting insulin-producing cells into a person with T1D can restore normal
blood glucose control! However, to prevent their immune system from killing those transplanted cells, the
individuals must take drugs that weaken their immune systems. This effectively trades one condition (T1D) for
another (a weakened immune system). The immunosuppressive drugs currently available are not only expensive
but they also have side effects, including high blood pressure, tremors, decreased kidney function, and increased
risk of infections and certain cancers. NE COE scientists are also studying other challenges transplanted cells might
face- like infections and toxicity from certain blood chemicals either of which can be shown to impair their insulin
producing capacity.
Our goal is to genetically modify the insulin-producing cells to evade the immune system, eliminating the need for
immunosuppressive drugs after transplantation. This is challenging because the human body naturally rejects
organs or tissues from another person. Moreover, in people with T1D, their immune system has already attacked
their own insulin-producing cells – a process called autoimmunity. This makes cell survival after transplantation
even more difficult.
We're approaching this goal in several unique ways:
1. Examining the approximately 20,000 genes in human cells to determine which ones to activate or deactivate
so the insulin-producing cells can avoid immune system attacks and be more resilient to other stressors.
2. Testing how inflammation, infections, and blood chemicals affect insulin producing cell function to understand
the stressors that may lead to insulin-producing cell death.
3. Exploring metabolic pathways and metabolites with new methods to minimize damage and optimize insulin producing
cell survival.
4. Pursuing a method to protect cells from oxygen deprivation during the transplantation process.
One novel approach involves specific proteins (enzymes) that control processes within insulin-producing cells. Our
studies have shown that drugs inhibiting these enzymes can make the insulin producing cells more resilient to
stresses, including those from the immune system, but also from infections, and harmful blood chemicals. Some
NE COE experts are designing oral medications to block these enzymes, potentially creating healthier insulin producing
cells. As an added benefit, the drugs we're developing to improve insulin-producing cell health in the
cells we transplant, could potentially prevent T1D in individuals identified as at-risk before the disease develops. It
is important to point out that the drugs we’re developing do not appear to have any direct effect on the immune
system leaving it unbridled from all the good functions it serves- like protection from infectious diseases and
cancer.
To speed up research that would otherwise take years and cost billions of dollars if done in humans, we've
developed "humanized mice." These special mice have no immune system but can live normally in a germ-free
environment. We can make these mice diabetic by triggering a "self-destruct" mechanism we’ve inserted into their
insulin-producing cells. We can then transplant human insulin-producing cells into these mice which at least
temporarily cures their diabetes to test our various approaches to protect the insulin production when we also
transplant into the mice a human immune system or provide the mice with other stresses like infections.