Potential new focus for MODS treatment

Although a definitive explanation for why multiple organ dysfunction system (MODS) occurs has yet to be found, solutions for treating it are beginning to emerge. Paloma Giangrande, PhD, associate professor in Hematology, Oncology and Blood and Marrow Transplantation, is senior author on a study published last month in Nature Communications investigating the treatment of MODS using aptamers to neutralize extracellular histones that could otherwise cause capillary leaks, hemorrhaging, and other systemic inflammations.

“Severe cellular injuries, which occur following conditions like stroke and autoimmune disease, cause histones to be released into circulation, eventually leading to MODS,” the authors write. “Approximately 45% of patients who develop MODS will die due to acute secondary organ injury/failure . . . and others become physically or mentally impaired.”

However, the study reveals a neutralization technique aimed to resolve this issue.The research team used negative selection, where they selected negatively charged aptamers that are specific to binding the positively charged histones, but not to serum proteins. In their solution, aptamers were used to soak up the histones after they have been released into circulation.

Giangrande is principal investigator of the research team. Other members include Shambhavi Shubham, PhD, former post-doctoral researcher and current research scientist at Integrated DNA Technologies, and Kevin Urak, PhD, MS, former research fellow and current developmental scientist at Frederick National Laboratory for Cancer Research in Maryland.

“Since histones are highly positive-charged proteins, we were expecting to find aptamers that were capable of selectively binding and neutralizing to the histones, thus inhibiting the progression of MODS,” Urak said.

The idea to investigate a possible solution for MODS stemmed a few years ago from a speech delivered by Charles Esmon, PhD, an adjunct professor in the Departments of Biochemistry, Molecular Biology and Pathology at the University of Oklahoma, on the effects of negatively-charged histones on MODS. Giangrande and her colleague Francis Miller, MD, at Duke University, exchanged ideas from this speech.

“Currently, there are no available drugs to neutralize the extracellular histones,” Urak said. “So Francis, who has collaborated with Paloma on several other projects, thought that negative-charged aptamers would be an excellent therapeutic approach for the binding and neutralization of these positive-charged proteins.”

Nature Communications covers ground-breaking research from all topics of natural sciences. As a high-quality, open access journal, a publication in this journal is a positive acknowledgement in the field of medicine.

“I have a name in the aptamer research community, so this publication potentially opens doors for start-up companies to develop these findings. This publication enables us, Francis Miller and I, to apply for funding for other projects,” Giangrande said.

Other researchers who contributed to this study include University of Iowa’s Giselle Blanco, Li-Hsien Li, Justin P. Dassie, William Thiel, Vijay Sonkar, Shubha Murthy, Wade Gutierrez, Yani Chen, and Julia Klesney-Tait. Jonathan Stiber and Beilei Lei at Duke University also assisted Miller in with the research he contributed to the study.