Robin Cotton, MD, is one of only nine physicians since 1960 to receive the William Cooper Procter Medallion, the highest honor bestowed by Cincinnati Children’s

Robin Cotton, MD.The award was created in 1960 by A. Ashley Weech, MD, chair of Pediatrics at Cincinnati Children’s from 1941 to 1963. Albert Sabin, MD — inventor of the oral polio vaccine — was the first recipient. The most recent recipient was Jeff Whitsett, MD, honored in 1996 for his role in developing artificial surfactant, which has dramatically improved survival rates for preterm infants.

Cotton, who recently stepped down as director of Pediatric Otolaryngology / Head and Neck Surgery, built the world’s premier center for diagnosing and treating airway abnormalities at Cincinnati Children’s. The center serves more than 33,000 outpatients and performs more than 11,000 procedures a year.

Tom Cody, the chairman of the board at Cincinnati Children’s, announced the honor on November 26. “Dr. Cotton is a remarkable innovator, surgeon, educator and leader, whom families from around the world have traveled to see for tracheal reconstruction surgery.”

Past Winners of the William Cooper Procter Medallion

  • Albert Sabin, MD
  • Ashley Weech, MD
  • Robert Lyon, MD
  • Edward Pratt, MD
  • Josef Warkany, MD
  • Waldo Nelson, MD
  • William Schubert, MD
  • Jeff Whitsett, MD

Breakthroughs, cures will come only from better funding of pediatric cancer research

John Perentesis, MD.We are pleased to highlight in this issue of Research Horizons some of the important research advances being made by scientists and doctors in the Cancer and Blood Diseases Institute at Cincinnati Children’s.

We have one of the largest and most successful pediatric cancer and blood disease research programs in the country. Cincinnati Children’s stands out as one of only a few centers nationally to have robust research that helps advance the understanding and treatment of childhood cancers and blood diseases.

More than half our patients come from across the nation and around the world for specialized cancer therapies and bone marrow transplantation. Much of our research focuses on understanding the genetic causes of pediatric cancers and blood diseases. We use this understanding to develop more effective, targeted therapies that attack diseases at their source, while minimizing the impact on a child’s healthy development.

The stories in this issue help illustrate why Cincinnati Children’s is one of the nation’s top two centers in overall pediatric research funding from the National Institutes of Health. Our faculty regularly wins prestigious and competitive national research awards.

But research funding for childhood cancer and blood disease remains an overwhelming challenge. The National Cancer Institute (NCI) works hard to advance cures for children and adults, but its budget pales in comparison to the economic burden of cancer on our society because one of every two men, and one out of three women, will develop cancer.

Just 3 to 4 percent of the NCI’s annual budget of $5 billion is dedicated to childhood cancers. The pharmaceutical industry spends about $70 billion on research and development each year. Seventeen to 18 percent of that is allotted to adult cancer and less than 1 percent goes to pediatric cancer.

Although this comparatively smaller investment in childhood disease does slow progress, the funds we receive are put to maximal use. Research has led to the cure of more than 80 percent of children with cancer, and as the articles featured here show, we are on the cusp of even greater breakthroughs every day. These new findings would advance much faster with better funding.

This is why we encourage fellow scientists, researchers and parents to speak out for enhanced funding of research into childhood cancer and blood diseases, as well as research on behalf of all childhood diseases. Our children’s futures depend on it.

John Perentesis, MD
Executive Co-Director, Division of Oncology
Cancer and Blood Diseases Institute

Cancer and Blood Diseases Institute Executive Co-Directors

Stella Davies, MBBS, PhD, MRCP, and Lisa Filipovich, MD
Bone Marrow Transplantation and Immune Deficiency Research

Joseph Palumbo, MD
(Acting), Hematology

Yi Zheng, Phd
Experimental Hematology and Cancer Biology

Experimental therapy crosses blood brain barrier to treat neurological disease

Dao Pan, PhD.Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood brain barrier in mice.

Posted online in the Proceedings of the National Academy of Sciences (PNAS) early edition on February 4, the study was led by Dao Pan, PhD, a researcher in the Cancer and Blood Diseases Institute at Cincinnati Children’s.

“This study provides a noninvasive procedure that targets the blood brain barrier and delivers large molecule therapeutic agents to treat neurological lysosomal storage disorders,” Pan says. “Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson’s and Alzheimer’s.”

Pan and colleagues assembled the new agent by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a L iduronidase (IDUA). They then treated lab-cultured human cells and mouse models of the disease mucopolysaccharidosis type I (MPS I).

MPS I is one of the most common lysosomal storage diseases to affect the brain. The disease can lead to hydrocephalus, learning delays and other cognitive deficits.

In MPS I, cells lack the IDUA enzyme, allowing cellular debris to accumulate in the brain and other organs. The experimental therapy is exciting because the team found a way to carry supplemental IDUA across the blood brain barrier. By tagging some apoE components to the IDUA enzyme, the modified protein could attach to endothelial cells and cross through the cells to reach brain tissues.

More research is needed to determine if the therapy can be applied to humans. The team also is exploring whether other brain disease can be treated using this new approach.

Gene test may become new weapon against septic shock

Hector Wong, MD. Hector Wong, MD, director, Division of Critical Care Medicine, has been awarded a three-year, $1.5 million grant from the National Institute of General Medical Sciences to pursue new ways to battle septic shock, one of the leading causes of death among hospitalized children.

An estimated 20,000 to 42,000 children a year suffer severe sepsis in the United States and about 4,500 children a year die, according to a study recently published in Critical Care Research and Practice by Cincinnati Children’s researchers Carley Riley, MD, and Derek Wheeler, MD.

Although survival rates have improved dramatically since the 1960s, better ways to detect the early signs of sepsis are needed to further reduce deaths.

“Through this new grant, our research program has evolved to a new phase,” Wong says. “By leveraging genomic data, we can develop new diagnostic tools for septic shock that can enhance decision making in the ICU, support quality improvement work and help identify candidates for clinical trials.”

Regulating protein could prevent scarring and inflammation. Findings have implications for heart failure, muscular dystrophy and pulmonary disorders

Researchers at Cincinnati Children’s have discovered a previously unknown function for a protein that could lead to new drugs for battling inflammation and tissue fibrosis.

The study finds that heart attacks and other types of injury activate a tissue repair pathway controlled by the protein TRPC6. The protein prompts cells called fibroblasts to change into myofibroblasts, which in turn secrete extracellular matrix, an important substance needed for tissue remodeling. Over activating this pathway can lead to excessive inflammation and scarring.

The study, led by Jeffery Molkentin, PhD, and Jennifer Davis, PhD, of the Heart Institute at Cincinnati Children’s, was published September 27, 2012, in Developmental Cell.

“Our study suggests that a TRPC inhibitor could be a good ant fibrotic or anti-inflammatory agent in heart failure, muscular dystrophy, pulmonary disorders and other diseases where tissue fibrosis becomes a problem,” Molkentin says. “Meanwhile, activation of the TRPC pathway with an agonist compound could be used in select situations to enhance wound healing.”

Prior to the new findings, TRPC6 had not been associated with fibrosis, although it has been linked to other cellular functions in skin cells, kidneys and the brain.

Some TRPC inhibitors already are in early stage development, although their initial design has not targeted heart disease, inflammation or fibrosis. The new study may expand the development focus, Molkentin says.

Mangano named Chief of Pediatric Neurosurgery

Francesco Mangano, DO. Francesco Mangano, DO, has been named chief of the Division of Pediatric Neurosurgery at Cincinnati Children’s. He served as acting director prior to this appointment.

Mangano joined the division in 2005 and has been instrumental in helping develop the medical center’s nationally renowned Pediatric Epilepsy Program. His research projects include investigating advanced MRI imaging techniques in children with congenital hydrocephalus and diffusion tensor imaging of hydrocephalus, traumatic brain injury, and vascular and neoplastic brain lesions.  He also is an expert in complex disorders of the spine and spinal cord.

Mangano earned his Doctor of Osteopathy degree from the Philadelphia College of Osteopathic Medicine; completed neurosurgery residency at Long Island Jewish Medical Center; and completed a neurosurgery fellowship at St. Louis Children’s Hospital.

Nephrology named NIH Center of Excellence

Prasad Devarajan, MD.Cincinnati Children’s Division of Nephrology has been named an NIH Center of Excellence in pediatric nephrology. The honor went to only three pediatric nephrology centers nationwide.

Collaboration among disciplines is a major requirement of the $4 million, five-year award, as is serving as a resource to individuals around the world who are conducting research into pediatric kidney disease.

“Our goal is to tackle some of the most vexing and difficult problems afflicting children with kidney disease worldwide,” says Principal Investigator and Division Director Prasad Devarajan, MD.

The division is known for research and clinical treatment of acute kidney injury, nephrotic syndrome and lupus nephritis. One breakthrough discovery is a biomarker test that identifies kidney injury early, before serious damage occurs. Center of Excellence funding will further the study of biomarkers to predict a child’s vulnerability to kidney problems due to disease or treatment.

The award will fund staff in Cincinnati Children’s core Genomics, Proteomics and Biomarker laboratories who are focused on kidney disease. These staff will help develop new biomarkers and build basic science models; their findings will serve as a resource to doctors and researchers.

The goal is to use the Center of Excellence award to help change the course of a childhood killer.

“People used to think that children died with acute kidney injury, but we now know beyond the shadow of a doubt that children die because of acute kidney injury,” Devarajan says. “It is a complication of the therapies we give our patients, and of advanced disease in other organ systems. It has generated an epidemic all over the world, and we need to put an end to it.”

Anti-rejection drug everolimus shrinks kidney and brain tumors, shows promise for a growing number of disorders

David Franz, MD.An important Phase III clinical trial confirms that the anti-rejection drug everolimus can dramatically reduce brain tumor growth in patients with tuberous sclerosis complex (TSC).

The study — published online November 14, 2012, in The Lancet — was led by David Franz, MD, director of the TSC Clinic at Cincinnati Children’s.

“Every patient in this study experienced a decrease in size of their tumors, and no patient required surgery for their tumors after treatment with everolimus,” Franz says. “Thirty-five percent of patients in this study on everolimus had at least a 50 percent reduction in tumor volume after an average of 42 weeks on medication.”

Until recently, surgery was the standard therapy for treating subependymal giant astrocytomas (SEGAs), but everolimus offers a new alternative, Franz says.

Similar results from a smaller Phase II study of everolimus were published in 2010 in The New England Journal of Medicine. Based on that data, the U.S. Food and Drug Administration (FDA) granted accelerated approval of everolimus for patients with SEGAs. The FDA had already approved using the drug to treat TSC related kidney tumors, based on studies by John Bissler, MD, a nephrologist at Cincinnati Children’s.

About 1 million people worldwide live with TSC, including nearly 50,000 in the US. The TSC Clinic at Cincinnati Children’s, which follows more than 800 children and adults, is believed to be the largest in the world.

Everolimus also may have benefits beyond treating TSC. The same mTOR signaling pathway associated with overactive cell growth in TSC also is implicated in Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, Huntington’s disease and autism. This makes everolimus, an mTOR inhibitor, a potential candidate to treat these disorders, Franz says.

Everolimus is marketed by Novartis, which provided drug and financial support for the study. In addition, several of the Phase III study co-authors are employees of Novartis.

Antommaria heads newly launched Ethics Center

Armand Antommaria, MD, PhD, FAAP.As rapid advances in medical research and clinical care turn the impossible into the everyday, navigating the intricacies of healthcare decision-making is increasingly difficult.

So the appointment of Armand H. Matheny Antommaria, MD, PhD, FAAP, as director of the new Ethics Center at Cincinnati Children’s seems all the more timely.

The Ethics Center will support clinicians, researchers and administrators in weighing the ethical implications of healthcare and research options. Antommaria will lead programs in clinical, research and organizational ethics, provide education to staff and conduct research on behalf of the center.

Antommaria, a general pediatrician, will spend about one-third of his time in clinical service as a hospitalist at Cincinnati Children’s, something he sees as essential to his ethicist role.

“Ethics should be an adjunct to clinical activities,” he says. “It should grow out of our clinical experience.” His work as a pediatrician first sparked his interest in healthcare ethics.

“Particularly in an institution like Cincinnati Children’s, where so many of the children have rare and complex conditions, there are ethical considerations in many of the decisions doctors and families must make,” he says. He points to left ventricular assist devices and bio repositories as just two areas where rapid advances have raised important ethical questions.

He hopes to help with those decisions, drawn here by what he terms a real “openness” to discussing and addressing the difficult issues that accompany progress.

Antommaria earned his MD at Washington University School of Medicine in St. Louis, and his PhD in religious ethics at The University of Chicago Divinity School. He completed his pediatric residency at the University of Utah. Before coming to Cincinnati Children’s, he served as associate professor of pediatrics and led ethics activities at Primary Children’s Medical Center in Salt Lake City.

He has published a variety of articles that include organ donation after circulatory death, critical care triage and other ethical issues in journals including JAMA and the Hastings Center Report.

Cincinnati Children’s receives Autism Center of Excellence grant

Darcy Krueger, MD, PhD.A network of five leading medical centers, led by Cincinnati Children’s Hospital Medical Center and Boston Children’s Hospital, has received a five-year, $12.5 million grant from the National Institutes of Health (NIH) to learn more about how autism develops.

The study, headed by Darcy Krueger, MD, PhD, will enroll 150 children under the age of 3 who have tuberous sclerosis complex (TSC), a rare genetic disease that causes tumors to form throughout the body, including the brain.

About 50 percent of children with TSC develop autism or autism-like symptoms. These children offer a unique way to study autism because TSC can be diagnosed even before birth, making it possible to observe how the brain’s circuitry develops before autism becomes apparent.

“If we can intervene before the onset of autism symptoms, we can perhaps offset future problems,” Krueger says.

This project is one of several ways researchers at Cincinnati Children’s are working to improve treatment for children with autism spectrum disorders. The projects range from refining the definitions of autism-like conditions to exploring the genetics of brain development to testing potential treatments.

Through the newly formed TSC Autism Center of Excellence Research Network (TACERN), and in close collaboration with the national Tuberous Sclerosis Alliance, researchers in the Autism Center of Excellence will track infants diagnosed with TSC using advanced brain imaging techniques.

Also participating in the study are the University of Alabama at Birmingham, Mattel Children’s Hospital at UCLA and the University of Texas Medical School at Houston.

Researchers discover gene linked to deafness

Saima Riazuddin, PhD, (right) with Zubair Ahmed, PhD.A team led by researchers at Cincinnati Children’s has isolated a genetic mutation responsible for deafness associated with Usher syndrome type 1.

Usher syndrome causes deafness, night blindness and a loss of peripheral vision through the progressive degeneration of the retina. The findings, published online September 30 in Nature Genetics, could lead to improved treatments.

Researchers conducted genetic analysis of 57 people from Pakistan and Turkey to pinpoint a gene mutation affecting the CIB2 protein that is associated with Usher syndrome type 1 and nonsyndromic hearing loss.

The CIB2 mutation appears to interfere with normal calcium signaling that regulates the ear’s ability to convert the mechanical energy of hair cells into electrical signals that the brain can recognize as sound.

“With this knowledge, we are one step closer to understanding the mechanism of mechano-electrical transduction and possibly finding a genetic target for future therapies,” says Zubair Ahmed, PhD, the study’s lead investigator. 

Saima Riazuddin, PhD, co-led the study. Others involved include Thomas Friedman, PhD, and Inna Belyantseva, MD, PhD, from the National Institute on Deafness and other Communication Disorders; and the teams of Suzanne Leal, PhD, of Baylor College of Medicine; and Gregory Frolenkov, PhD, of the University of Kentucky.