TREATING DEADLY GUT DISEASE IN PREMATURE BABIES

Premature babies face a host of medical challenges at birth, but none as deadly and mysterious as a disease called necrotizing enterocolitis (NEC). The condition creates an inexplicable combination of inflammation and infection that causes parts of the intestine to die. NEC progresses at a ruthless speed, leaving physicians with few options -- typically supportive care, emergency surgery or antibiotics. Only half of newborns who undergo surgery survive, and they often face serious life-long complications.

"In the fifty years since necrotizing enterocolitis was first identified, we've accomplished relatively little to change its devastating course. Even worse, we don't know which babies will get it. One minute, a child can appear healthy, but then be dead from NEC hours later," said Gail Besner, MD, chief of pediatric surgery at Nationwide Children's Hospital.

That may be about to change thanks to two major breakthroughs driven by Besner and Surgeon-in-Chief at Nationwide Children's R. Lawrence Moss, MD.

After nearly two decades of work, their separate efforts have yielded both the discovery of a biomarker that can help predict which babies will get the disease, as well as treatments that can restore the intestine's natural ability to protect itself against NEC.

"These researchers' advances offer innovative approaches to necrotizing enterocolitis that may someday make it a more predictable and better managed complication of prematurity," said John Barnard, MD, President of the Nationwide Children's Research Institute and Pediatric Director of The Ohio State University Center for Clinical and Translational Science (CCTS).

Growth factors, stem cells offer gut protection

For Besner, the key has always been to prevent NEC before it can start. In the 1990's, she began looking closely at what was happening at the molecular level to an immature bowel in the throes NEC. Besner made a major discovery, observing that a protein called heparin-binding EGF-like growth factor (HB-EGF) -- which she initially discovered -- played a life and death role in protecting premature infants from NEC.

In numerous studies, Besner showed that without HB-EGF, the structures within the intestines that maintain barrier function and integrity, including a massive network of nerves and blood vessels, became easily injured and beyond repair. The addition of HB-EGF had the opposite effect, helping protect intestines from injury in animal models of NEC.

From that molecular level understanding of NEC, Besner developed a bigger picture hypothesis about how the nerve damage within an immature gut impacted the disease's development and progression -- and where a solution might be found.

"It is fascinating that we have more nerves in our gut than in our brain, and the 'heart' of our immune system is actually in our intestines," said Besner, who also is a professor of pediatrics and surgery at Ohio State's College of Medicine and holds their H. William Clatworthy Jr. Professorship in Surgery. "We found that NEC seriously disrupts the gut's nervous system both short and long term. In fact, the immature nervous system of the premature infant's intestine may actually predispose the baby to developing NEC in the first place. That revelation opened to door to consider stem cell therapy to restore nerves needed for the gut and possibly other organ systems dysregulated by NEC to function properly."

The work, published in Stem Cell Research and Therapy, earned her the 2013 BioMed Central Research Award in Translational Medicine. It also provided the foundation for a series of studies showing that intravenous or even intraperitoneal administration of neural stem cells or mesenchymal stem cells could heal tissue damage in animal models of NEC. Besner also found that the healing effect was magnified when HB-EGF was administered at the same time as stem cells, or when stem cells were genetically manipulated to overexpress HB-EGF.

"The different types of stem cells effectively migrated to where the intestines were injured, preventing further damage and inflammation, and helped heal the wound. The transplantation of neural stem cells also appears to repair neural functionality of the gut in ways that could help prevent long term digestive issues that are so common among babies who survive NEC," said Besner.

While the results are encouraging, Besner notes that no treatment will be truly useful until doctors can actually identify which babies are at the highest risk for developing NEC. And that's where she says Moss's research is the perfect complement to her discoveries.

"The idea that we could prevent NEC with stem cells is exciting, but we can't give that therapy -- or any therapy for that matter -- to every premature baby," said Besner. "Moss' research is the critical key to making prevention and treatment practical and possible."

"We were asking the wrong questions"

Prevention of NEC wasn't initially top of mind for Moss. Instead, the clinician-scientist began researching a question that had plagued surgeons for years: of the two types of surgical procedures commonly used to treat NEC, which one had the better outcomes? To find the answer, Moss' team initiated a randomized clinical trial. This approach was the first of its kind to answer questions regarding surgical therapy for infants with a life threatening problem. The results of this study shocked the surgical community.

"It turned out that both procedures had the same survival rate. And that rate wasn't where we wanted it to be anyway," recalled Moss, who is also the E. Thomas Boles, Jr. Professor of Surgery at Ohio State's College of Medicine. "That's when I realized we were asking the wrong question. We needed to intervene before these babies required surgery. The only effective way to do that was to predict which babies were going to get NEC in the first place."

As a first step, Moss began exploring risk factors associated with the prevention and development of NEC, conducting some of the largest multicenter prospective NEC studies ever done. Teaming up with five other university-based pediatric teaching hospitals, including Yale, Stanford and Johns Hopkins, Moss helped create an algorithm for clinicians to use which would identify those children at greatest risk for getting and dying from NEC. The algorithm was based on a combination of laboratory and clinical findings -- but Moss and his colleagues realized this algorithm was not able to predict which babies were at greatest risk of NEC with sufficient accuracy.

This led the researchers to investigate the technique of combining biologic date from each individual patient with the clinical algorithm. They started by analyzing tens of thousands of proteins in the urine of children who had suspected NEC or sepsis -- a type of systemic infection. The group identified seven proteins that could potentially indicate the presence and severity of NEC. Most recently, the group combined the use of these biomarkers with the algorithm and determined the combination was able to predict prognosis of children with NEC with up to 90% accuracy.

"There is definitely more work we need to do to refine the way we could use the biomarker, the algorithm or the combination of the two," said Moss. "But after so many years of not being able to reassure parents, of not having real solid evidence to base my clinical choices on -- I feel like we're headed in the right direction."

Pushing the boundaries of NEC knowledge

Both investigators acknowledge that despite the intense need, the challenges of getting a new therapeutic or diagnostic test to children are substantial. Regulatory and economic factors surrounding pediatric drug approvals make many manufacturers hesitant to invest the resources needed to bring a new drug or device to market.

Moss says that's where support, like the kind provided by the CCTS, has been critical to helping researchers build a solid foundation of science showing that large scale clinical trials based on their work would likely yield effective therapeutics.

"Federal funding and support from the CCTS has enabled us to create an environment that lets ideas flourish and allows us to help patients while keeping in touch with the bench science that can change those patients' lives," says Moss. "Without that, we would not be in this place today where we have a realistic hope that we will soon be able to say -- we know how to identify which babies are going to get NEC, and we think we know how to stop it before it ever starts."

Both scientists hope that clinical trials using the biomarker and/or stem cell therapies will initiate within the next five to eight years. In the meantime, both investigators continue to redefine the boundaries of current NEC knowledge. Moss is leading a multi-institutional study to validate biomarkers that can detect the onset of a deadly systemic infection in children with NEC. Besner is exploring the long term effects of NEC on overall neurodevelopment. She is also working with regenerative medicine experts at Nationwide Children's and The Ohio State University to develop tissue scaffolds that use a child's own cells to regrow and replace sections of damaged or diseased bowel.

"I am hopeful that I will not go through yet another decade of telling parents that I don't know if their child will survive surgery," says Besner. "Instead, I am looking forward to telling those parents -- 'It looks like your baby is at risk for developing NEC. We have something that can protect him, and he's going to be OK."