Novel combination therapy promotes wound healing

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Credit: Sharp Lab/Albert Einstein College of Medicine

October 25, 2018–(BRONX, NY)–By incorporating a gene-suppressing drug into an over-the-counter gel, researchers at Albert Einstein College of Medicine and their colleagues cut healing time by half and significantly improved healing outcomes compared to control treatments. Results from the combination therapy, which was tested in mice, were published online today in Advances in Wound Care.

"Not only did wound healing occur more rapidly and completely, but actual regeneration occurred, with hair follicles and the skin's supportive collagen network restored in wounded skin–clinically important improvements that are unprecedented in wound care," says senior author David J. Sharp, Ph.D, professor of physiology & biophysics at Einstein. "We foresee this therapy having broad application for all sorts of wounds, from playground cuts to battlefield injuries to chronic wounds."

Chronic wounds alone affect 6.5 million Americans and cost $25 billion in annual healthcare costs. Over the past several decades, few advances have been made in treating wounds of any type.

In 2015, Dr. Sharp and colleagues discovered that an enzyme called fidgetin-like 2 (FL2) puts the brakes on skin cells as they migrate towards wounds to heal them. He reasoned that reducing FL2 levels might enable healing cells to reach their destination faster. So he and his colleagues developed small interfering RNA molecules (siRNAs) that specifically inhibit the gene that codes for FL2. When the siRNAs were encased in nanoparticles and sprayed on skin wounds in mice, the treated wounds healed faster than untreated wounds.

In the current study, Dr. Sharp enhanced the siRNAs' wound-healing potential by combining them with PluroGel–a protective gel that keeps wounds moist and has antimicrobial properties when applied to bandages and other wound dressings. In addition, Dr. Sharp incorporated the siRNAs into microparticles made of collagen, a naturally occurring protein that readily releases its siRNA "cargo" after coming in contact with the skin.

The FL2-siRNA/PluroGel combination was applied to mice with either skin excisions or burns. For comparison, studies involving both types of skin injuries also used two control groups: mice treated with PluroGel alone and mice treated with PluroGel plus siRNA that did not target the gene for FL2. Wounds were treated on the day of the skin excision or burn and again two, four and six days later. For 14 days following the injuries, wounds were assessed by investigators who were "blinded" as to the treatment the mice received.

On the fourth day after mice treated for excision wounds, the open wound areas of mice in the two control groups were nearly twice as large as the wound areas in mice treated with the FL2-siRNA/PluroGel combination. Several mice treated with the combination therapy also had hair follicles present in the wound zone, while no such structures were seen in the control mice.

For mice treated for burns: by 14-days post injury, the wounds of mice in both control groups were more than one-third larger than in the mice treated with the FL2-siRNA/PluroGel combination. In addition, the burn wounds of all mice treated with the FL2-siRNA/PluroGel combination had closed completely by day 14; by comparison, 25 percent and 30 percent of treated wounds in the PluroGel and PluroGel/nontarget siRNA control groups, respectively, remained unhealed at that time.

"These results show that FL2-siRNA plus PluroGel is a highly promising wound treatment," says Adam Kramer, a Ph.D. candidate in Dr. Sharp's lab and co-lead author. "By lowering FL2 levels in skin cells, the FL2-siRNA helps cells reach wound sites much faster than they ordinarily would–essential for minimizing scarring and preventing wounds from becoming chronic. And by hydrating wounds and inhibiting microbes, PluroGel offers important additional wound-healing benefits."

Dr. Sharp and Brian O'Rourke, Ph.D., the paper's co-lead author and chief scientist at MicroCures, Inc., have achieved similar success in treating skin wounds in pigs–animals with skin that closely resembles human skin. Dr. Sharp's team plans to seek permission from the U.S. Food and Drug Administration to test their wound-healing therapy in clinical trials.

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The paper is titled "Fidgetin-like 2 siRNA Enhances the Wound Healing Capability of a Surfactant Polymer Dressing." Einstein authors also included Hillary Guzik, M.S., and Joshua Nosanchuk, M.D. Other authors were Longyue Cao, M.D., Ph.D., (formerly of Einstein) of Boston Children's Hospital, Jayakumar Rajadas, Ph.D., and Mohammed Inayathullah, Ph.D., both of Stanford University.

MicroCures has licensed the technology described in this paper from Einstein. Dr. Sharp is the inventor of the technology and is the founder and chief scientific officer at MicroCures. Dr. Nosanchuk is a science advisor for MicroCures.

About Albert Einstein College of Medicine

Albert Einstein College of Medicine, part of Montefiore, is one of the nation's premier centers for research, medical education and clinical investigation. During the 2017-2018 academic year, Einstein is home to697 M.D. students, 181 Ph.D. students, 108 students in the combined M.D./Ph.D. program, and 265 postdoctoral research fellows. The College of Medicine has more than 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2017, Einstein received more than $174 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States through Montefiore and an affiliation network involving hospitals and medical centers in the Bronx, Brooklyn and on Long Island. For more information, please visit http://www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook and view us on YouTube.

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