- Type 1 diabetes is an autoimmune disease, where the body's immunity destroys the insulin-producing beta cells
- Beta cells contain a protein called renalase that makes them more functionally prone to becoming a target of the immune system
- Targeting renalase therapeutically, makes beta cells resistant to autoimmune attack, protects them against stress, and helps preserve them
Targeting a protein called renalase can protect the insulin-producing cells in the pancreas known as beta cells against an autoimmune attack. Type 1 diabetes is an autoimmune disease where the body's immunity attacks and destroys the insulin-producing beta cells in the pancreas.
The faulty production of insulin leads to an increase in sugar level in the blood, causing diabetes. Though researchers have successfully grown large volumes of beta cells, protecting these cells from immune attack is still under study.
Joslin Diabetes Center researchers now have found an unusual strategy that eventually may help to protect such transplanted beta cells or to slow the original onset of the disease.
An existing FDA-approved drug, pargyline, inhibits renalase and increases the beta-cell survival in lab models.
The functional problems with beta cells themselves may trigger the autoimmune attack in type 1 diabetes, say Kissler and Yi, who is an assistant investigator in the Islet Cell and Regenerative Biology Section. "You might have genes that make the beta-cell a little bit dysfunctional and more prone to becoming a target of the immune system," Kissler explains.
A beta cell line from a non-obese diabetic (NOD) mouse that mimics type 1 diabetes was used for the study. The researchers then tried to inhibit the genes across the beta-cell genome, one at a time, using a screening technique based on the CRISPR gene-editing method. Inhibiting the genes led to the deletion of the protein renalase which made the beta-cells resistant to autoimmune attack.
"Whole-genome CRISPR screening is a powerful tool for new target discovery, and we hoped that it would help us find any mutations that protect the beta cell," Yi says.
The CRISPR screen for surviving beta cells produced the gene for renalase, which previous research had shown is associated with type 1 diabetes.
The researchers then created NOD mouse beta cells, some with the renalase gene functionally "knocked out" and some not. They transplanted these cells to NOD mice with autoimmune diabetes. They found that the intact beta cells had died off but those cells with renalase knocked-out, survived.
"This was a very black-and-white research model," Kissler comments. "If the cells aren't protected, they're gone.".
Response from T immune cells spreaheaded the autoimmune attack on beta cells, and the study showed that one type of T cell was less likely to attack the renalase knock out cells compared to normal beta cells.
The researchers also saw that the renalase mutation was protecting mouse beta-cells against a condition called endoplasmic reticulum (ER) stress.
To replicate the study in human cells, the team joined with Douglas Melton of the Harvard Department of Stem Cell and Regenerative Biology to create human beta cells for similar tests in a dish "Again, we saw that the renalase knockout protected cells against ER stress," Kissler says.
Pargyline, a drug approved by the Food & Drug Administration almost 60 years ago, is used to treat hypertension. This drug is found to have an inhibitory effect on renalase.
On testing pargyline in their mouse transplant model, the Joslin researchers found that the drug protected beta cells extremely well also against ER stress. In experiments with human cells, pargyline also displayed a protective effect.
In the next step, researchers hope to test pargyline in a pilot clinical trial to see if it slows the progress of new-onset type 1 diabetes in a small number of patients.
"Since it's FDA-approved and the drug is safe, this would be the best approach to test if the protection we observed in mice and human cells will hold true in people," Kissler remarks.