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Variant of Peptide Now in Trials for Wound Therapy Could Limit “Bystander Effect” Damage in Heart Attacks; Group Hopes to Develop Exosome-Based Approach to Delivery of Potentially Protective Peptide

Imagine there were a drug that you could take soon after a heart attack that could reduce damage by protecting healthy heart muscle tissue. "Cardiologists say that when a heart attack occurs, time is muscle," said Robert Gourdie (photo), PhD, Director of the Fralin Biomedical Research Institute at VTC (Virginia Tech Carilion) Center for Heart and Reparative Medicine Research. Without oxygen supplied by blood flow, heart cells die -- quickly. But while a heart attack may only reduce blood and oxygen to an isolated section of heart cells -- causing what's called hypoxic ischemic injury -- those dying cells send signals to their neighbors. "The problem is that the area of dying tissue is not quarantined. Damaged heart cells start to send out signals to otherwise healthy cells, and the injury becomes much bigger," said Dr. Gourdie, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Regenerative Medicine Research and Professor in the Department of Biomedical Engineering and Mechanics in the Virginia Tech College of Engineering. Scientists sometimes call this spread of injury signals to nearby healthy tissues a "bystander effect." But what if there were a way to keep the injury localized to the group of cells that are directly affected by the hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact? A study published online on August 19, 2019 in the Journal of the American Heart Association reveals that a new molecule developed by a team of researchers led by Dr. Gourdie could help preserve heart tissue during -- and even after -- a heart attack. The open-access article is titled “Interaction of α Carboxyl Terminus 1 Peptide with the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia‐Reperfusion Injury.” Nearly a decade ago, Dr. Gourdie, in collaboration with a postdoctoral fellow in his lab, Dr. Gautam Ghatnekar, stumbled across a promising discovery. Dr. Gourdie's team discovered a compound that targets the activity of channels in cell membranes responsible for controlling key aspects of the bystander effect. But the compound, called alphaCT1, also had other unexpected and beneficial effects, particularly in relation to skin wound healing. "We found that it helped reduce inflammation, helped heal chronic wounds such as diabetic foot ulcers," said Dr. Gourdie. Recognizing the compound's potential, Dr. Ghatnekar and Dr. Gourdie founded a company, FirstString Research Inc. (https://firststringresearch.com/), to commercialize alphaCT1, which is now in phase III clinical trials for treating wounds.

Meanwhile, Dr. Gourdie has been trying to understand how the drug works on a molecular level, which led to the study just published in the Journal of the American Heart Association.

"This paper asks the question: how does this peptide drug actually work?" said Dr. Gourdie.

The Gourdie group designed molecules with slight chemical differences from the parent molecule, which led to an unexpected discovery. One of the alphaCT1 variants -- called alphaCT11 -- showed more potency than the parent molecule.

"AlphaCT11 seems to be even more effective than the original peptide in protecting hearts from ischemic injury similar to those occurring during a heart attack," said Dr. Gourdie.

The newly published study reveals that alphaCT11 gives a robust injury-reducing effect, even when given 20 minutes after the loss of blood flow that causes ischemic injury. When put to the same test, the parent peptide did not appear to provide a heart-protective effect when administered after ischemic injury.

"AlphaCT11 could provide the basis for a new way to treat heart attacks and prevent the spread of damage that occurs immediately after a heart attack," said Dr. Gourdie.

The researchers perfused isolated laboratory mouse hearts, keeping the organ alive and beating for a number of hours. Ongoing studies, through collaboration with Virginia Commonwealth University's Dr. Antonio Abbate and Dr. Stefano Toldo, will examine how alphaCT11 performs in live mice.

EXOSOME-BASED DELIVERY

Dr. Gourdie is also developing new methods for delivering alphaCT11 using naturally-derived tiny lipid droplets called exosomes. These newer experiments could provide a stepping stone toward clinical trials in patients who have suffered a heart attack.

STUDY CONTRIBUTORS

The lead co-authors, Dr. Jingbo Jiang, pediatric cardiologist at Shenzhen Children's Hospital in China who did her doctoral work at Virginia Tech, and Dr. Daniel Hoagland, a postdoctoral research associate, both worked in Dr. Gourdie's lab on the study.

Other contributors to the newly published research included Dr. Joseph Palatinus, a cardiology fellow at Cedars-Sinai who did his doctoral research in Dr. Gourdie's lab; Jane Jourdan, lab manager at the Center for Heart and Reparative Medicine Research; Dr. Geert Bultynck and Dr. Jegan Iyyathurai, who work at KU Leuven; Dr. Zhiwei Zhang of the Guangdong Cardiovascular Institute; Dr. Zhen Wang and Dr. Kevin Shey, who work at Vanderbilt University; Ryan King, a Translational Biology, Medicine, and Health graduate student at Virginia Tech; Dr. Steven Poelzing, an Associate Professor at the Fralin Biomedical Research Institute; and Dr. Huamei He and Dr. Francis McGowan, who work at the Children's Hospital of Philadelphia.

[Press release] [Journal of the American Cardiology Association article]

IMAGE

Robert Gourdie, PhD, Professor at the Fralin Biomedical Research Institute at VTC, is working on a way to limit the damage of hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact. (Credit: Virginia Tech).