The future of medical devices that correct heart problems in infants and children lies in Philadelphia and Israel. At least, that’s the goal of a new, groundbreaking research agreement.

Philadelphia’s former Mayor Michael A. Nutter and Jerusalem’s Mayor Nir Barkat witnessed the signing of a research collaboration among The Children’s Hospital of Philadelphia, Drexel University and The Hebrew University of Jerusalem. The initiative will explore ways to improve problematic medical devices for infants and children with heart defects and congenital heart disease (CHD).

The agreement, signed in Jerusalem by former CHOP CEO Steven M. Altschuler, MD, Drexel President John A. Fry, and The Hebrew University of Jerusalem President Menahem Ben-Sasson in November 2014, established a research consortium and the creation of two interdisciplinary “dream teams” of investigators. The three institutions are contributing $250,000 over two years to each team, demonstrating their entrepreneurial spirit and commitment to the collaboration. Outside investors interested in the commercial viability of advancing pediatric translational research are also being recruited.

One “dream team” is based at CHOP and is conducting a research project entitled “Pediatric Transcatheter Valve Replacements: Preventing Device Failure Due to Structural Degeneration.” The team, led by CHOP’s Robert J. Levy, MD, is focusing on Tetralogy of Fallot (TOF), a rare condition caused by the combination of four heart defects. Infants with TOF are known as “blue babies” because their blood doesn’t contain enough oxygen as a result of the cardiac defects.

Repairing TOF requires cardiac surgery early in life, but the procedure leaves the young patients with a chronic malfunction of their pulmonary valve. Currently, the best option to treat the malfunction is transcatheter pulmonary valve (TPV) therapy, in which an artificial heart valve is implanted to replace the defective one. Unfortunately, CHOP researchers have found that the device is prone to oxidative damage and structural failure.

The team is charged with gaining a better understanding of what causes the oxidative and structural damage, as well as what’s behind the early inflammatory responses to the TPV. The researchers hope to use their findings to modify the TPV material with an antioxidant to prevent damage.

Joining Dr. Levy, who is also a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, are Matthew Gillespie, MD, of CHOP and Joseph H. Gorman, MD, and Robert C. Gorman, MD, of the University of Pennsylvania. Also on the team are Kenneth Barbee, PhD, and Kara Spiller, PhD, of Drexel, and Gershon Golomb of The Hebrew University.

The largest collaborative study to date on the genetic roots of childhood epilepsies is bringing new hope to sufferers of the most severe forms of the central nervous system disorder. An international team of researchers, including pediatric neurologist Dennis Dlugos, MD, director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and a professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania, have identified specific gene mutations that cause difficult-to-treat forms of epilepsy.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” Dr. Dlugos said. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

For many patients with severe epilepsies, the cause of the seizures cannot be identified but increasing evidence indicates that genetic factors may play a role. Epilepsies affect up to 3 million patients in the U.S. and up to one-third of all epilepsies are resistant to treatment with antiepileptic medication.

In a study released in November 2014 and reported in The American Journal of Human Genetics, researchers identified gene mutations associated with severe epilepsy syndromes called epileptic encephalopathies, which disrupt functioning in the brain’s synapses, the junctions at which nerve cells communicate with one another. The research team pinpointed the gene mutations by sequencing the exomes contained in the human genomes of 356 patients with severe childhood epilepsies as well as the exomes of their parents. An exome is made up of the human genome’s exons, which are the coding parts of the genes.

Using family-based exome sequencing, the researchers identified 429 mutations that appeared in affected children, but not in their parents. Such mutations are called “de novo” mutations. It’s important to note that, while de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes necessarily cause disease.

Perhaps the most surprising and promising finding, researchers discovered that a mutated version of a gene called DNM1 present in five of the patients had a clear connection to the way the patients’ synapses functioned. This finding, said Dr. Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he noted.

Multiple researchers from the U.S. and Europe participated in the project. Two international research consortia collaborated on the study: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke, and the European EuroEPINOMICS consortium.

The Children’s Hospital of Philadelphia has become the first hospital in the world to offer human leukocyte antigen (HLA) genotyping, an advanced research tool with the potential to change how immunological and infectious diseases are treated. CHOP is making the test available through a new partnership with ARUP Laboratories of Salt Lake City, Utah, which will provide HLA testing using next-generation sequencing (NGS) methods to its customers.

In February 2014, CHOP researchers announced the development of a unique laboratory test to characterize the genes that encode HLA molecules. HLAs are complex, highly variable proteins on the surfaces of cells that are essential to immune function. HLA genes are the most complex gene family in the entire human genome, which presented challenges for previous testing methods.

The new procedure provides a cutting-edge tool for research in immunological diseases, infectious diseases, and pharmacogenomics, and may help improve transplantation. ARUP, a nonprofit enterprise of the University of Utah’s Department of Pathology, will use the test to help aid decisions in bone marrow transplantation. ARUP offers more than 3,000 tests and test combinations, ranging from routine screening tests to highly esoteric molecular and genetic assays,” according to its website.

HLA genotyping “addresses a 60-year old problem,” said Dimitri S. Monos, PhD, director of CHOP’s Immunogenetics Laboratory and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. Since the discovery of HLAs in the early 1950s, it has been a challenge to accurately and thoroughly characterize HLA gene sequences. We have now used NGS tools to significantly advance HLA genotyping. This is the first technology that gives results free of any current or future ambiguities.

Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief, who is also a professor of Pathology and Laboratory Medicine at Penn, added, “We are pleased to be able to provide this test to ARUP Laboratories’ customers. It allows us to provide greater access to our tests.”

Adults of all ages suffer from pulmonary hypertension (PH), a serious condition that results from high blood pressure in the arteries of the lungs. Over time, the pulmonary arteries narrow, making the right side of the heart work harder. PH also complicates a number of different disease processes, including congenital heart disease, chronic lung disease of prematurity, and genetic disorders. In other cases, the cause of PH may be unknown.

PH doesn’t sound like a condition that would affect children. Indeed, PH is a relatively rare problem in pediatrics, but the frequency of the diagnosis in children and PH-related hospitalizations is actually rising. The Children’s Hospital of Philadelphia’s pulmonary hypertension program follows more than 650 children and adolescents with PH.

Unfortunately, there is currently no cure or FDA-approved therapy for pediatric PH. However, a grant from the National Heart, Lung, and Blood Institute in April 2015 positions CHOP at the forefront of efforts to advance pediatric PH research and change the future for children with PH and their families.

CHOP is one of nine pediatric centers, all members of the Pediatric Pulmonary Hypertension Network (PPHNet), to receive the grant in order to build a much-needed informatics registry of children with PH. The grant’s purpose is significant because many of the current care practices for children with PH are based on findings from adult studies. For example, clinicians do not know if a 13-year-old whose PH stems from a genetic mutation and starts medicines earlier than a 35-year-old with the exact same genetic mutation will have a longer, better life, noted Brian Hanna, MDCM, PhD, the director of CHOP’s pulmonary hypertension program.

“We still have more questions than answers,” said Rachel Hopper, MD, an attending cardiologist in pulmonary hypertension at the CHOP Cardiac Center and assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Who gets pulmonary hypertension? Why do they get pulmonary hypertension? Why do some children with hypertension improve over time, while others will end up needing a lung transplant? We need to collaborate as practitioners to pool enough data to answer those questions.”

On its own, an individual pediatric PH center would not be able to gather information for a large enough number of children with PH. But the PPHNet registry will provide a shared infrastructure and standardized data collection in a single resource so that investigators can evaluate specific outcomes for a group of patients who share the same condition. For example, the PPHNet registry could help researchers determine the response of children with PH to certain therapies.

The grant project will also address concerns that registries tend to be expensive to run because they require diligent maintenance to ensure that the data is precisely collected and valid for research. The PPHNet project will explore if it is possible to obtain the same type of data using computer software to scour electronic health records. Researchers will compare the value of both the software and traditional methods and determine whether the data generated produces the same results.

As they figure out the most efficient and accurate way to collect and store registry information about children with PH, researchers also hope to gain important insights into the causes, clinical course, and diagnostic approaches to the diverse conditions associated with PH that will lead to better treatment.

“The concept of pooling and precisely phenotyping children is going to make a huge difference,” said Dr. Hanna, who is also a clinical professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “A key thing is that we eventually will be able to make diagnoses and conduct research protocols all the same way. We’ll be able to advance the science faster and understand it better, so that we’ll be to answer questions about pediatric pulmonary hypertension.”

Why has the human immunodeficiency virus (HIV) that causes AIDS been so difficult to eradicate?

Researchers from The Children’s Hospital of Philadelphia and Temple University want to help solve that puzzle by exploring potential methods to boost the immune system’s ability to attack HIV infection. Specifically, they are focusing on new ways to destroy HIV that lingers in brain cells despite conventional antiviral treatment.

CHOP and Temple received a $4.3 million, four-year NeuroAIDS grant from the National Institute of Mental Health (NIMH) in October 2014 to explore different biological pathways that make HIV so tenacious. The two institutions are collaborating with the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP, and Temple’s Comprehensive NeuroAIDS Center — two centers focused on mental health and HIV that are supported by the National Institutes of Health.

The co-principal investigators of the grant are Steven D. Douglas, MD, chief of the Section of Immunology at CHOP and a professor of Pediatrics at the University of Pennsylvania, and Jay Rappaport, PhD, professor of Neuroscience and Neurovirology at the Temple University School of Medicine. They are overseeing three separate research projects focusing on HIV that remains in brain cells after antiviral treatments.

The first project, led by Dr. Rappaport, focuses on the metabolism of ATP, which is the chemical that serves as energy currency in cells. Because HIV infection stimulates enzymes that break down ATP and weaken the body’s immune responses, Dr. Rappaport’s research team is studying drugs that may inhibit those enzymes.

The second project, led by Tracy Fischer-Smith, PhD, assistant professor of Neuroscience and Neurovirology at Temple, is studying immune polarization, in which cells called macrophages stop playing a protective role and start immunity-suppressing activities. The research team is concentrating on the “signaling proteins” that drive immune polarization, with the goal of counteracting those proteins’ disruptive signals in order to restore infection-fighting functions to immune cells.

The third project, led by Dr. Douglas, looks at “substance P,” a neuropeptide that plays a key role in stimulating inflammation during HIV infection. Dr. Douglas’ team hopes to prevent the virus from entering cell reservoirs by manipulating a cell receptor known as NK-1R that binds to substance P, thereby blocking the viral replication that causes HIV’s devastating effects.

The teams will spend the first two years of the grant determining which pre-clinical approaches are most likely to be successful when they begin studies using animal models in the third and fourth years. The goal of the animal studies is to demonstrate proof-of-concept for strategies that may lead to human trials of new HIV treatments.

Preterm birth, the leading cause of newborn death in the U.S., poses one of the most perplexing riddles in medical science. One in nine babies is born prematurely in the U.S., according to the March of Dimes, a rate that has remained frustratingly steady despite years of investigation.

The Children’s Hospital of Philadelphia has joined a new effort to change the future of premature birth by analyzing the causes to learn more about how to prevent it. CHOP is part of a transdisciplinary team established by the new March of Dimes Prematurity Research Center at the Perelman School of Medicine at the University of Pennsylvania. In a collaboration announced in February 2015, the research team is applying sophisticated technology and methodology in molecular biology and genomics to better understand preterm birth.

Babies born before 37 weeks are considered to be premature and, because their bodies and organ systems have not matured completely, they often need help for everything from breathing, eating, and fighting infection to simply staying warm. Preterm babies can have long-term health problems, including cerebral palsy, cognitive impairments, and sensory disorders.

The March of Dimes is investing $10 million over the next five years to create the Prematurity Research Center. More than 40 investigators are focusing on three key research themes to uncover important new findings about the causes of preterm birth: bioenergetics and genetics, cervical remodeling, and placental dysfunction. The research center at the Perelman School of Medicine is one of four created by the March of Dimes around the country. The other three centers are located at the Stanford University School of Medicine in California; a partnership of Ohio research centers in Cincinnati, Columbus, and Cleveland; and Washington University in St. Louis.

“This kind of cooperation and collaboration is on a different scale than has ever been developed for preterm birth,” said Rebecca A. Simmons, MD, the project leader for the bioenergetics and genetics theme and an attending neonatologist at CHOP and the Hospital of the University of Pennsylvania. “It’s not only collaborative across our campus and many different departments within the Penn/CHOP system, but we also collaborate between centers, which is a very unique structure.”

Deborah A. Driscoll, MD, the Luigi Mastroianni Jr. Professor and Chair of the Department of Obstetrics and Gynecology at the Perelman School of Medicine, is the director of the Prematurity Research Center. Dr. Simmons, the Hallam Hurt Professor of Pediatrics, and Samuel Parry, MD, associate professor of Obstetrics and Gynecology and chief of the Division of Maternal-Fetal Medicine at the University of Pennsylvania, serve as the research project’s principal investigators.

For the first research theme of bioenergetics and genetics, the March of Dimes is tapping CHOP researchers’ expertise in mitochondrial biology and biochemistry. Mitochondria are organelles often described as the body’s cellular power plants because they extract energy from nutrient molecules in order to perform cells’ most basic and critical functions. Dr. Simmons, along with Marni Falk, MD, director of the Mitochondrial-Genetic Disease Clinic at CHOP, and Neal Sondheimer, MD, PhD, an attending physician at CHOP, will investigate how impaired cellular metabolism could result in power shortages in the reproductive tract that contribute to preterm labor.

Researchers will look at reproductive tissues from mice and humans to identify any patterns of mitochondrial dysfunction. They will then see whether these disturbances interfere with the tissues’ ability to maintain bioenergetics and metabolic stability during pregnancy.

The center’s second theme ties into this hypothesis by exploring how the microbiome, a community of bacteria that normally inhabit the vagina and cervix, may influence cervical remodeling. A dynamic process during delivery, cervical remodeling transforms the cervix from a rigid structure into a pliable passageway for the baby.

Preliminary studies suggest that the microbiome is different in women who experience preterm birth. Accordingly, the researchers will explore whether the abnormal bacteria cause mitochondrial distress and inflammation that prematurely accelerates cervical remodeling. The cervical remodeling research will be led by Michal Elovitz, MD, associate professor of Obstetrics and Gynecology and director of the Maternal and Child Health Research Program at the University of Pennsylvania.

“If we do find changes in the microbiome, those are targets for therapeutics that can be developed,” Dr. Simmons, who is also a professor of Pediatrics at the Perelman School of Medicine. “We’ll look for strategies to either change the composition of the microbiome or change how the microbiome is functioning.”

The third research theme, led by Dr. Parry, focuses on placental dysfunction. Researchers will investigate mitochondrial deficiencies and an unhealthy microbiome as possible factors that disrupt metabolic processes in the placenta and lead to early labor.

Further, the researchers recognize that some of the answers to the medical mystery of preterm birth also may lie within complex gene-environment interactions. Therefore, the research teams plan to explore the evolving field of epigenetics, which is the study of mechanisms that change how genes are expressed without altering the underlying DNA sequence.

The teams hope to gain insights into the multiple pregnancy-related risk factors — biological, behavioral, social, physical, and environmental — that could cause epigenetic modifications. For example, Dr. Simmons will explore how any abnormalities in the genes and biochemical pathways that regulate mitochondrial metabolic function could have a role in preterm birth. “We think that if we can identify novel metabolic pathways, we can certainly design future interventions,” Dr. Simmons said.

As the Prematurity Research Center moves from the discovery phase to targeting and developing therapeutics, the researchers hope that their findings along the way will spark additional preterm birth studies. The center is offering a series of pilot grants to investigators to encourage them to tackle this important health challenge.