Geert W. Schmid-Schonbein, Ph.D.

Leading Biosciences hopes that its drug will keep digestive enzymes from spilling into the bloodstream and triggering the airway inflammation seen in COVID-19

COVID-19’s worst symptoms are felt in the lungs — where the airways of some patients fill with dead cells and fluid, triggering a deadly spiral of inflammation. A local biotech company thinks it can treat these symptoms by targeting a completely different part of the body: your gut.

Leading Biosciences received permission from the Food and Drug Administration on Friday to test whether its drug, designed to shore up the intestine’s natural barrier, helps severe COVID-19 patients breathe on their own and recover sooner.

It’s an unorthodox-sounding approach, but it’s based on the idea that many diseases — including COVID-19 — are connected to what happens in the gut… Continue reading.

The mechanisms for Type II diabetes with defective insulin receptors remain uncertain. A new protease activity technique shows digestive proteases and proteolytic receptor cleavage of the insulin receptor in man even after a single meal… Continue reading.

R. Mazor, D. Friedmann-Morvinski, T. Alsaigh, O. Kleifeld, E. B. Kistler, L. Rousso-Noori, C. Huang, J. B. Li, I. M. Verma, G. W. Schmid-Schönbein

Restoring leptin’s effects in obesity

Obesity is the most common metabolic disease in the developed world. Although obese individuals have increased plasma concentrations of the anorexigenic hormone leptin, they are refractory to its anorexigenic effect. Mazor et al. showed that, in rodents, obesity induced matrix metalloproteinase–2 (Mmp-2) activation in the hypothalamus. In turn, Mmp-2 activation reduced leptin-mediated signaling by promoting leptin receptor degradation. Mmp-2 deletion in the hypothalamus increased leptin receptor expression and reduced fat accumulation in mice fed a high-fat diet. The results suggest that targeting Mmp-2 might be an effective strategy for treating obesity by restoring the anorexigenic effects of leptin.

Abstract

Obesity and related morbidities pose a major health threat. Obesity is associated with increased blood concentrations of the anorexigenic hormone leptin; however, obese individuals are resistant to its anorexigenic effects. We examined the phenomenon of reduced leptin signaling in a high-fat diet–induced obesity model in mice. Obesity promoted matrix metalloproteinase–2 (Mmp-2) activation in the hypothalamus, which cleaved the leptin receptor’s extracellular domain and impaired leptin-mediated signaling. Deletion of Mmp-2 restored leptin receptor expression and reduced circulating leptin concentrations in obese mice. Lentiviral delivery of short hairpin RNA to silence Mmp-2 in the hypothalamus of wild-type mice prevented leptin receptor cleavage and reduced fat accumulation. In contrast, lentiviral delivery of Mmp-2 in the hypothalamus of Mmp-2−/− mice promoted leptin receptor cleavage and higher body weight. In a genetic mouse model of obesity, transduction of cleavage-resistant leptin receptor in the hypothalamus reduced the rate of weight gain compared to uninfected mice or mice infected with the wild-type receptor. Immunofluorescence analysis showed that astrocytes and agouti-related peptide neurons were responsible for Mmp-2 secretion in mice fed a high-fat diet. These results suggest a mechanism for leptin resistance through activation of Mmp-2 and subsequent cleavage of the extracellular domain of the leptin receptor… Click to view the Full Text… Continue reading.

San Diego, Calif., Dec. 15, 2015 — Waiting 30 seconds in between bites of food allows children to realize they’re no longer hungry before they overeat—preventing excessive weight gain. That’s the conclusion of a study published in the Dec. 15 issue of the journal Pediatric Obesity by an international team of researchers, including bioengineers at the University of California, San Diego.

The study is the first clinically controlled trial to test how effective eating slowly is for detecting that feeling of satiety–and losing weight, researchers said. The study monitored the eating habits of 54 children ages 6 to 17 in the city of Durango, Mexico for a year. The students were compared to a control group with similar demographics.

The slow eating approach has the advantage of being sustainable over the long term, unlike most diets, said Geert Schmid-Schonbein, a study co-author and bioengineering professor at the Jacobs School of Engineering at UC San Diego, because it doesn’t require you to change what you eat on a daily basis. It doesn’t deprive you of your favorite foods and it can be applied in any cultural and ethnic context.

“You can adopt this slow eating approach for yourself and keep it up for the rest of your life,” Schmid-Schonbein said. “You can teach this approach to your children and they can teach it to their children in turn.”

New research from the University of California, San Diego published in the Jan. 23 issue of Science Translational Medicine moves researchers closer to understanding and developing treatments for shock, sepsis and multiorgan failure. Collectively, these maladies represent a major unmet medical need: they are the number one cause of mortality in intensive care units in the United States, with hundreds of thousands of deaths annually. There is currently no treatment for these conditions in spite of many clinical trials.

Most researchers agree that organ failure in shock and sepsis involves the intestine – and that it arises when the mucosal barrier of the small intestine becomes permeable. However, the mechanism by which this disrupted membrane is tied to vastly different kinds of shock, as well as multiorgan failure and death has not been understood.

In the case of sepsis (septic shock), for example, some researchers speculate that bacteria in the intestine and their toxins are responsible for organ failure. However, interventions against bacteria that are aimed at reducing mortality in patients undergoing septic shock have been unsuccessful in clinical trials.

Looking more broadly than bacteria, a team of researchers led by Geert W. Schmid-Schönbein in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering has carried out several years of careful analysis of the events in shock. That research led them to investigate the powerful, concentrated digestive enzymes in the intestine, the same enzymes that are part of daily digestion.

Bioengineering research from the Jacobs School is at the center of a 200-patient Phase 2 clinical pilot study now under way. The trial is testing the efficacy and safety of a new use and method of administering an enzyme inhibitor to stop multi-organ failure in shock patients.

This new use of an FDA-approved drug is based on decades of research by bioengineering professor Geert Schmid-Schönbein on the microvascular and cellular reactions that lead to multiorgan failure after a patient has gone into shock, which is the second-leading cause of in-hospital deaths in the United States.

Schmid-Schönbein and his colleagues discovered that under conditions of shock, the epithelial cell barrier that lines the small intestine becomes permeable causing potent digestive enzymes to be carried into the wall of the intestine, bloodstream and lymphatic system where they digest and destroy healthy tissue, a process he named autodigestion. His method of blocking the enzymes with an enzyme inhibitor was licensed to InflammaGen Therapeutics in 2005. The company has since developed the InflammaGen Shok-Pak, a drug/delivery platform that delivers the drug through a nasogastric tube directly into the stomach and lumen of the intestine.

Four engineering faculty members with technology transfer success stories discussed the challenges of the commercialization process during a March 14 dinner celebrating the 10th anniversary of the von Liebig Center for Entrepreneurism and Technology Advancement. The von Liebig Center offers seed funding and advisory services and is part of the Jacobs School of Engineering at the University of California, San Diego.

A 200-patient Phase 2 clinical pilot study will be initiated this month to test the efficacy and safety of a new use, and method of administering, an enzyme inhibitor for critically ill patients developed by University of California, San Diego Bioengineering Professor Geert Schmid-Schönbein. Conditions expected to qualify for the study include new-onset sepsis and septic shock, post-operative complications, and new-onset gastrointestinal bleeding.

This new use of a Food and Drug Administration-approved drug is based on decades of research by Schmid-Schönbein on the microvascular and cellular reactions that lead to multi-organ failure after a patient has gone into shock, which is the second-leading cause of in-hospital deaths in the United States.

Schmid-Schönbein and his colleagues at the UC San Diego Jacobs School of Engineering discovered that under conditions of shock, the epithelial cell barrier that lines the small intestine becomes permeable causing potent digestive enzymes to be carried into the bloodstream and lymphatic system where they digest and destroy healthy tissue, a process he named Autodigestion. The treatment involves blockading the enzymes with an enzyme inhibitor.