“Currently there are no effective preventive or treatment strategies for pancreatitis; it’s a disease that’s been difficult to understand,” says Baoan Ji, M.D., Ph.D., cancer biologist on Mayo Clinic’s Florida campus.
This may be changing.
In a new publication, co-senior authors Dr. Ji and Mayo gastroenterologist Yan Bi, M.D., Ph.D., with collaborators at Mayo and Cedars-Sinai Medical Center, describe a series of discoveries aimed at developing the first targeted treatment for pancreatitis.
Of mice and mechanisms
The lack of treatment options for pancreatitis has been attributed to the absence of an animal model capable of mimicking human pancreatitis, Dr. Ji explains. Previous attempts at creating a model involved inserting smaller segments of human genes into mice, which resulted in low gene expression unable to cause the disease observed in humans.
In an attempt to solve this, the researchers inserted into mice a full-length version of the most commonly mutated human gene in hereditary pancreatitis, PRSS1R122H .
“Using a full-length gene can better resemble a human-like version of the condition in an animal model,” Dr. Ji says. “Unlike gene segments, the full-length gene contains all of the regulatory components to achieve an appropriate level of gene expression.”
The Mayo team tested its new model and found it to be robust and applicable to humans, rendering it suitable for further experiments.
Armed with a relevant model, the investigators were then able to assess potential mechanisms by which pancreatitis can develop. The culprit: increased activity of trypsin, a digestive enzyme in the pancreas. Experts have long suspected that trypsin activity could be the mechanism behind pancreatitis, but were unable to test it definitively without an appropriate animal model.
If increased trypsin is responsible for the development of pancreatitis, as these findings suggested, medicine capable of inhibiting the enzyme would be a promising starting point for treatment.
In this portion of the study, mice with induced pancreatitis were given an FDA-approved blood thinner, also known to have anti-trypsin effects, twice daily for a week. The researchers found that the treatment was able to halt disease progression.
Through further experiments, the team revealed that the anticoagulant (blood thinning) properties of the drug were key. Coagulation and inflammation pathways frequently interact with one another, the researchers explain. Coagulation is thought to contribute to pancreatitis, but past trials using anticoagulation drugs alone have not shown strong treatment benefits. Similarly, anti-trypsin drugs alone show only limited therapeutic effects. The scientists in this animal study discovered that the synergy of anticoagulation and trypsin inhibition resulted in this drug’s effectiveness for pancreatitis therapy.
While the model developed in this work focused on the hereditary type of pancreatitis, Dr. Ji and colleagues also studied mice without the PRSS1 R122H mutation and saw promising effects, leading them to believe their findings are applicable to pancreatitis more generally.
“Patients who show up in the clinic with this condition can be offered supportive care such as fluids, painkillers, and antibiotics if necessary, but physicians are rather helpless to cure it or prevent its recurrence,” says Dr. Bi. “We started with basic research and made a discovery that can be readily moved into clinical trials. This study is another example of Mayo’s bench-to-bedside research focus, and we’re hopeful that its translation to patient care can happen quickly.”
Importantly, the scientists believe their novel animal model will advance patient care as it provides the capability to develop and test additional drugs for pancreatitis therapy and pancreatic cancer prevention.
The study was published in The Journal of Clinical Investigation. It was funded by the U.S. Department of Defense with additional partial support from the National Institutes of Health.