Vijay P. Singh, MBBS
Can you describe your drug development project?
We have identified pancreatic lipases as being responsible for lipolysis of visceral fat and thus worsening the outcomes of acute pancreatitis, a disease I have studied for more than 15 years. In this project, we aim to identify agents that are selective inhibitors for pancreatic lipases and have good bioavailability. The only lipase inhibitor currently approved by the Food and Drug Administration, orlistat, is an oral formulation with poor systemic bioavailability.
We aim to do a high-throughput screen of a library of about 400,000 compounds to identify agents that selectively inhibit pancreatic lipases. We expect about 1 percent of these chemicals will be efficacious. We will then exclude the ones with nonspecific targets and test the remaining ones for their efficacy in reducing cell death induced by acute lipotoxicity resulting from the action of pancreatic lipases on fat.
What motivated you to get involved in this work?
Pancreatitis is the most common gastrointestinal cause of hospitalization in the United States. It has no targeted therapy. Over the years, I have developed a passion to develop such a therapy.
Patients with pancreatitis typically present after the onset of severe abdominal pain, which heralds an attack. While the attacks resolve within a week in most patients, about 25 percent have a severe attack. When severe, large areas of the pancreas die or the patient develops renal and respiratory failure, which can result in death.
Over the last few decades, it has become increasingly clear that obese patients are more likely to have severe pancreatitis. On exploring the pathophysiology of this in detail, we universally note that it is the breakdown of the excess abdominal fat in obese patients by pancreatic lipases that contributes to these severe outcomes.
Fat is normally stored as triglyceride, each molecule of which has three fatty acids covalently linked to a glycerol backbone. Pancreatic lipases leaked out of the damaged pancreas cleave off the fatty acids, liberating three fatty acids for every triglyceride molecule. Obese patients with the excess pounds of adipocyte triglyceride have a large release of fatty acids, which causes worse outcomes.
What do you hope to accomplish with this project?
We aim to inhibit the deleterious pathway mentioned above by developing a drug that will be able to inhibit the pancreatic lipases from degrading the excess fat. We will thus be able to potentially abort a severe attack and help patients with this devastating condition.
How do you see this project eventually improving patient care?
We believe that patients who present early in the course of the disease and can potentially develop severe acute pancreatitis would be the ones to benefit the most from such therapies. While the eventual route of delivery cannot be predicted, potential routes include oral, IV or direct application to the tissue surrounding the pancreas.
Another situation where this may be beneficial is in therapy of patients who have already developed severe necrosis and are often in organ failure. Such patients require multiple drainages of the pancreatic necrosis over several weeks. Local application of a lipase inhibitor at the initial intervention may help improve the clinical course of such patients and reduce morbidity.
How has the CCaTS Drug Discovery and Development resource aided your work?
In collaboration with Sanford-Burnham, we will be potentially able to move this forward in a successful manner. With Sanford-Burnham doing the high-throughput screen and narrowing the potential drugs into a few hundred, my lab at Mayo Clinic's campus in Arizona, along with the lab of my Mayo colleague Nathalie Meurice, Ph.D., can do the more detailed testing of these potential agents. Thus, we will be able to achieve our goals with this collaborative effort.