���ϸ�����

An experimental compound reduced the cell death, inflammation, and organ damage seen with diabetes.

Led by ���ϸ����� Langone Health researchers, a new study in mice showed that a drug candidate prevented the interaction between two proteins, RAGE and DIAPH1, a coupling that enables heart and kidney injury seen with diabetes, and slows the healing of related wounds.

, the work shows that by keeping DIAPH1 from attaching to RAGE, the study compound reduces swelling in tissues affected by diabetes and drives faster tissue repair. Experiments in both human cells and mice found that the experimental drug significantly reduced short-term and long-term complications of type 1 and type 2 diabetes. Called RAGE406R, the drug tested is a small molecule named for the protein it targets.
    
“There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can—not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE,” said co-senior study author , the Dr. Iven Young Professor of Endocrinology at ���ϸ����� Grossman School of Medicine and a member of the in the . “If confirmed by further testing in human trials, the compound could potentially fill gaps in treatment, including the fact that most current drugs work only against type 2 diabetes.”

Harmful Interaction

RAGE is a receptor, a type of protein that interacts with signaling molecules called advanced glycation end products (AGEs). Created when proteins or fats attach to sugars in people with diabetes, AGEs build up in the blood of those with diabetes and obesity, and as part of normal aging.

Experiments showed that the RAGE406R compound competes for the site on RAGE that would otherwise be occupied by DIAPH1, which builds actin filaments that form part of the cell’s skeleton. The research team showed that DIAPH1 attaches inside cells to the tail end of RAGE. This DIAPH1-RAGE complex then increases the formation of actin structures that worsen diabetic complications.

Previously, Dr. Schmidt’s team screened a library of more than 58,000 molecules and found a subset that competitively inhibited RAGE-DIAPH1 signaling. Its prior lead drug candidate, RAGE229, failed a standard test that detects if a drug has structure that may possibly change DNA code to create cancer risk. RAGE406R effectively eliminates the risk-creating part of RAGE229’s structure.

The team tested RAGE406R in a lead model of chronic diabetes complications, which is impaired wound healing in obese mice with type 2 diabetes. The data revealed that in both male and female diabetic mice, topical treatment with RAGE406R accelerated wound closure.

The results revolve around the body’s immune system, which recognizes and destroys invading bacteria and viruses. This system’s activation causes inflammation—responses such as swelling that result from immune cells homing in on sites of infection or injury. Many diseases, including diabetes, feature misplaced inflammation. RAGE406R lowered levels of a key proinflammatory immune signaling chemical, the chemokine CCL2, which damped down inflammation in immune cells called macrophages. This in turn increased tissue structural changes that occur as part of healing.

“Our findings point to a promising new pathway for treating diabetes in the future,” said co-senior study author Alexander Shekhtman, PhD, a professor in the Department of Chemistry at the State University of New York (SUNY) at Albany. “The current study results serve as a springboard for the development of therapies for both types of diabetes, and for designing markers that can measure how well the new treatment works in live animals.”

Along with Dr. Schmidt, authors from the Diabetes Research Program within the Department of Medicine at ���ϸ����� Langone Health are co-first author Michaele Manigrasso, along with Gautham Yepuri, Kaamashri Mangar, and . Other ���ϸ����� Langone authors are ,in the Department of Medicine, as well as Yanan Zhao and , in the Division of Biostatistics in the Department of Population Health. Along with Dr. Shekhtman, authors from the Department of Chemistry at SUNY at Albany include first author Gregory Theophall and Parastou Nazarian, along with Aaron Premo, Sergey Reverdatto, and David Burz. Robert DeVita, PhD, from RJD Medicinal Chemistry and Drug Discovery Consulting LLC, was also a study author.

This work was supported by U.S. Public Health Service grants 1R24DK103032, 1R01DK122456-01A1, P01HL146367, and 5R01GM085006. The ���ϸ����� Histology Core is partly supported by Perlmutter Cancer Center support grant P30CA016087. Support was also provided by the Diabetes Research Program at the ���ϸ����� Grossman School of Medicine. Dr. Manigrasso, Dr. Ramasamy, and Dr. Schmidt are named on patent applications owned by ���ϸ����� Langone Health that cover the work detailed in the current study manuscript. The study authors’ relationship to this intellectual property is being managed in accordance with the policies of ���ϸ����� Langone Health. Dr. DeVita, a consultant for ���ϸ����� Technology Opportunities & Ventures’ Therapeutics Alliances and for Intercept Therapeutics, was compensated for this project. 

About ���ϸ����� Langone Health

���ϸ����� Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient, Inc., has ranked ���ϸ����� Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. ���ϸ����� Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.