Using CRISPR technology, scientists have created transplants of pancreatic cells that can treat type 1 diabetes and control blood sugar levels in mice, while avoiding detection by the immune system.
Unlike previous transplants, their treatments are based on engineered pancreatic cells that can treat diabetes without the need for drugs that suppress the immune system. These drugs lead to many serious side effects and must be taken for life, making them a major safety hazard for patients.
The study, published in the April 12 issue of Science Translational Medicine, could tackle many of these safety concerns and address an obstacle that has held back the use of pancreatic islet transplants in the clinic.
"Eliminating the need for insulin administration and reversing diabetes with normalization of blood glucose levels, and doing this without immunosuppression, would be a transformational advance for patients," said Sonja Schrepfer, senior vice president at Sana Biotechnology Inc. and senior author of the new study.
A More Permanent Solution for Diabetes
Approximately 1.9 million people in the U.S. have type 1 diabetes, according to the American Diabetes Association. Type 1 diabetes develops when the pancreas fails to produce enough insulin to control blood sugar, largely because the body's own immune cells start damaging pancreatic cells.
Although the condition was once almost always fatal, the use of insulin starting 100 years ago transformed the disease into a chronic and manageable disorder, Schrepfer said.
Despite the availability of insulin today, the lack of a cure or a long-term solution still leaves patients with a high risk of severe health consequences from hypoglycemia, or low blood sugar.
For example, as many as 25% of patients with type 1 diabetes have "hypoglycemia unawareness," and have trouble telling when their blood sugar levels are getting low, according to a 2018 study. These patients have a far higher risk of hypoglycemic events, which only grow more common over time.
Glucose monitoring devices can help catch these hypoglycemic events and assist patients with controlling their blood sugar by providing readings in real time. Although patients appreciate these devices, the technology still doesn't cure the condition, nor does it remove the uncertainty and daily self-management that patients face.
A more permanent solution involves transplants of clumps of pancreatic cells, or islets. With this approach, researchers take islets of functional pancreatic cells and transplant them into the pancreas of a patient with type 1 diabetes.
Some initial studies show that islet transplants can replace a patient's own malfunctioning pancreatic cells and can control blood sugar and protect against hypoglycemic events for years at a time. Therefore, islet transplants could offer patients a longer-term solution compared with insulin injections or glucose-monitoring devices.
However, islet transplants have a high rate of complications because they provoke responses from the immune system. This forces patients to take immune-suppressing drugs, which come with a range of severe side effects that limit patients' quality of life.
"Allogeneic islet transplantation — transplantation from a separate donor — replenishes the vanished pancreatic islet cell population and provides glucose control," Schrepfer said. "However, patients need life-long immunosuppression to protect the islet grafts from allogeneic — and autoimmune — rejection, which causes side effects such as kidney toxicity, infections and cancer."
Engineering Transplants to Hide from Immune Cells
With a background in transplant immunology and transplant surgery, Schrepfer has dedicated decades to finding solutions to make pancreatic islets and other types of transplants safer and more tolerable for patients.
In this study, she worked with Xiaomeng Hu, a researcher at Sana Biotechnology and lead author of the new study. The pair led a team of scientists who studied whether it would be possible to reduce or even eliminate the need for immune-suppressing drugs after islet transplants.
The researchers theorized they could engineer transplanted pancreatic cells to hide from the immune system, which would minimize the risk of immune reactions damaging the transplanted islets.
To do this, they took advantage of CRISPR gene editing techniques to modify human pancreatic cells and render them "hypoimmune." They first removed genes that produce two proteins named class I and class II MHC, which normally trigger responses from the immune system.
As a second layer, the scientists also engineered the pancreatic cells to display extra quantities of CD47, an immune signaling protein. CD47 works as a "don't eat me" flag that tells immune cells to avoid engulfing and destroying healthy cells.
When transplanted into mice with type 1 diabetes, the islets of engineered cells successfully controlled blood sugar levels. The islets also avoided being killed by the immune system's macrophages and natural killer cells, even without the use of immune-suppressing drugs.
As an extra precaution, the researchers also designed the hypoimmune pancreas cells with a sort of "safety switch" to eliminate them if needed. By blocking the protective CD47 protein with an antibody, they could render the transplanted cells vulnerable to being killed by immune cells.
"By overcoming the allogeneic — and autoimmune — barrier in islet transplantation, this platform could be used for cell transplantation approaches in a number of disease settings," Schrepfer argued.
The new islet transplants haven't been tested in humans yet, so more data is needed before Schrepfer's team can make conclusions about their longevity in patients. However, she believes there is no reason the cells would survive for less time than islet transplants that are currently used in the clinic.
The researchers also caution that their study didn't examine whether the islets could avoid activating the immune system over longer periods of time, and call for further work in larger animal models before moving into humans.
But these next steps are already on the way. The scientists are conducting studies in humans to determine how viable their hypoimmune islet cells are as well as expanding their technique to other cell therapies such as cancer-killing CAR T cells.