Bench to Bedside

September 2014

Breakthrough Work Leads to Rare Bone Disease Trial


As rare pediatric diseases go, Fibrodysplasia Ossificans Progressiva (FOP) is about as rare and debilitating as rare diseases come. Affecting approximately one in two million people around the world, FOP is a condition in which ectopic (extraskeletal) bone is formed when “muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone,” according to the NIH’s Genetics Home Reference page. FOP is caused by a congenital mutation in a gene called ALK2.

Over time, this ectopic bone — also known as heterotopic ossification (HO) — becomes pervasive and widespread and eventually restricts FOP patients’ ability to move, speak, and feed themselves, and can lead to near-total paralysis and early death. In addition, there is a non-genetic form of HO that is not as severe as FOP and can occur in individuals of any age.

Like so many rare diseases, there are few treatment options for FOP because its rarity means it has been studied by fewer research groups and has attracted less research money than more common conditions. In the U.S., a disease is considered rare if it affects fewer than 200,000 people, so FOP — of which there are roughly 300 cases in the U.S. — is one of the very rarest rare diseases.

Fibrodysplasia Ossificans Progressiva “is an extremely serious disease,” said CHOP’s Maurizio Pacifici, PhD, who often hears from families desperate to find a treatment for FOP.

Dr. Pacifici is among a group of CHOP Orthopaedics’ Investigators — including Masahiro Iwamoto, DDS, PhD and Motomi Enomoto-Iwamoto, DDS, PhD — who have been working to better understand and ultimately treat FOP. Their many years of work may soon pay off, because a drug they identified as a possible FOP treatment is now in a phase II clinical trial to treat FOP.

FOP is marked by “flare-ups”— localized swelling and inflammation — that signal the development of ossification in the affected area. Currently, the only approved treatment for FOP is to give patients steroids when they experience flare-ups. The steroids reduce inflammation and swelling, but are not able to prevent ossification and can also have considerable side effects. Because FOP patients are prone to getting multiple flare-ups, at times with little respite between episodes, their steroid treatments’ side effects can be compounded, Dr. Pacifici pointed out.

All of which has spurred the search for a safer, more effective treatment for FOP and HO. Unlike FOP, HO is not confined to a small community of patients with a genetic mutation in ALK2. HO “can happen to any of us,” Dr. Pacifici pointed out, because the condition can be brought on by any number of causes, such as trauma, invasive surgeries, and burns, as well as prolonged immobilization. Because severe trauma is such a strong inducer of HO, it was seen in some 65 percent of seriously wounded soldiers during the peak of recent wars, creating major difficulties for the soldiers’ physical recovery and return to service as studies by U.S. Department of Defense (DoD) investigators showed.

Palovarotene: From Emphysema to FOP

Supported in large part by DoD funding, Dr. Pacifici and colleagues have been looking at ways to arrest HO (and by extension, FOP) for several years. They have also been collaborating with researchers from the military — particularly the Navy’s Jonathan Forsberg, MD, of the Walter Reed National Military Medical Center — who was the lead author of papers describing the incidence and clinical consequences of HO in wounded soldiers.

In 2011, the CHOP researchers’ investigations led to a paper in Nature Medicine showing that retinoic acid receptor (RAR) agonists inhibited chondrogenesis, or the development of cartilage, which is the first step in the formation of ectopic bone during HO and FOP. The team had previously shown, in a 2010 Journal of Orthopedic Research study on ectopic bone formation and HO, that RARs “are major modulators and regulators of skeletal development and function.”

In their Nature Medicine study, using mouse models of HO and FOP, the team — led by Drs. Iwamoto and Pacifici — found that several retinoid agonists were “potent inhibitors of trauma-induced intramuscular and subcutaneous HO and a genetic form of FOP.” In particular, they focused on RAR-γ agonists, finding that they “have the biological properties needed to interfere with the specific processes and mechanisms that are needed for the initiation and progression of heterotopic ossification and might therefore represent effective remedies, probably the most effective reported so far, for this condition and related ectopic ossification conditions.”

Moreover, the drugs all “seem to have minimal side effects,” the authors noted.

In an editorial that accompanied the Nature Medicine study, the University of Pennsylvania’s FOP Research Center’s Frederick S. Kaplan, MD, and Eileen M. Shore, PhD, said the CHOP group’s “tantalizing findings … suggest that successful, long-term inhibition of [HO] may be possible even a week or more after the inflammatory inductions events have occurred, an achievement that has not yet been realized by any other class of medications.”

One of the drugs the CHOP researchers identified was Palovarotene. Originally developed by the pharmaceutical company Roche to treat emphysema, Palovarotene was shelved when trials showed the drug was effective but not as effective as expected. Following the publication of the Nature Medicine paper, the Montreal-based startup Clementia Pharmaceuticals acquired the rights to develop Palovarotene to treat FOP in close collaboration with the CHOP Investigators.

Fast forward to today: In July, Clementia launched a phase II trial Palovarotene to treat FOP. When the trial was announced, Clementia’s Chief Executive Officer, Clarissa Desjardins, PhD, said, “We could not have arrived at this point without the support and collaboration of countless members of the FOP community including scientists, physicians, and most importantly patients and their families, who inspire our work everyday.”

“It is rare to go from basic science, and we really started with completely basic science, to a clinical trial, …it took us a long, long time to do it,” Dr. Pacifici noted. Palovarotene may turn to be an effective treatment for FOP in the pediatric and young adult population as well as HO in wounded soldiers and other affected individuals.

To read more about the basic and translational research work by the CHOP Orthopaedics’ investigators, use the following link to their CHOP Research Institute website.

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Mutation Helps Explain How Our Body Clock is Set


Most of us have failed to get enough sleep on a few occasions. Maybe it was as a college student studying for final exams, or as a new parent consoling an infant who is teething. Remember how you dragged through the next day in a bad mood and unable to focus?

Yet a few people who are considered to be natural “short sleepers” seem to function well under the same sleep-deprived circumstances. Researchers at The Children’s Hospital of Philadelphia are investigating why some of us seem to need more sleep than others. In a study published in the August issue of SLEEP, the study team described a new gene variant associated with short sleep and resistance to sleep deprivation in humans. Their findings support the hypothesis that genes related to circadian rhythms, in particular DEC2, can affect not only the timing of sleep, but also the magnitude of sleep homeostasis and sleep architecture.

Circadian rhythms control the biological clocks in our bodies. Homeostasis includes both short-term and long-term measures that the body uses to control and maintain an optimal internal environment.

“We found DEC2 is not only a circadian gene, but it is also related to homeostasis,” said Renata Pellegrino, PhD, senior research associate in the Center for Applied Genomics at The Children’s Hospital of Philadelphia, who collaborated on the study with an international study team. “That is why we are so excited. This gene could explain sleep length and how we respond to sleep deprivation, or why we some of us sleep for a certain number of hours a night and others don’t.”

The researchers sequenced circadian clock genes in a cohort of healthy young adult twin pairs with no chronic conditions. Out of 200 twins, they identified a DEC2 mutation in one sibling who during baseline testing slept an average of five hours per night — more than an hour shorter than his twin brother who did not carry the gene.

The study team performed a series of cognitive performance tests to see how attentive each brother was after spending 38 hours without sleep in the sleep lab. The twin with the gene mutation performed better on psychomotor vigilance compared to his brother.

During unrestricted recovery sleep for one night following the 38 hours without sleep, the twins underwent electroencephalography that showed their brains’ electroactivity throughout the major sleep phases — Stages 1, 2, 3, 4 and REM. Stage 3 is characterized by Delta waves, which are high amplitude brain waves associated with deep, restful sleep. Stage 3 sleep also is related to maintaining homeostasis after sleep deprivation or wakefulness. The twin with the DEC2 mutation made more Delta waves and stayed in Stage 3 sleep longer than his brother.

The researchers went a step further to investigate how the DEC2 mutation interacted with other circadian clock genes. They discovered that the variant appears to alter the molecular mechanisms that set the duration of sleep that individuals need.

In the future, Dr. Pellegrino and her colleagues plan to form collaborations with researchers in other countries to see how common this variant is in other populations. They also would like to discover how the genes not only affect the brain, but also other body systems.

“True short sleepers in general are very resistant to sleep deprivation,” Dr. Pellegrino said. “They are very motivated and ready to go, so maybe the mutation protects you cognitively. But is there a price for that? We still don’t know the other metabolic effects.”

The study involved a collaboration among researchers from The Children’s Hospital of Philadelphia; the University of Pennsylvania School of Medicine; the Philadelphia Veterans Affairs Medical Center; Washington State University; Universidade Federal de Sao Paulo, Brazil; and Koc University, Istanbul, Turkey. The research was supported in part by grants from the National Heart, Lung, and Blood Institute, and the Institutional Development Fund from the Center for Applied Genomics at CHOP.

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Investigators Take Clinical Look at Teen Driver Safety


Crashes remain the leading cause of young adult death (ages 16 to 24) with four times the number of deaths from cancer and 38 times the number of deaths from the flu. In fact, a teen’s highest lifetime risk of crashing occurs immediately following the learner phase when beginning to drive without adult supervision.

A team of researchers at The Children’s Hospital of Philadelphia Research Institute’s Center for Injury Research and Prevention (CIRP), led by Flaura Koplin Winston, MD, PhD, is taking a new tactic by addressing novice drivers’ performance and risk management from a clinical standpoint.

“As a primary care pediatrician at Karabots, I see my role as helping families to anticipate and manage health issues and ensure their children can realize their full potential,” said Dr. Winston, scientific director and founder of CIRP. “When my research showed that motor vehicle crashes accounted for one-third of all teen deaths, I looked for protocols to include driving management in my practice, but I couldn’t find them. I could not even find a valid way to assess driving performance and risk.

“This is when I knew that CHOP could take a lead on bringing our science to bear in evidence-based, evaluated ways to help families manage this exciting but dangerous phase of an adolescent’s life,” Dr. Winston continued. “Each teen approaches the driving task with assets as well as challenges, and once we figure out what they are, then we can put into place a personalized care management plan.  Driving has a relatively small margin for error, and I want to do what I can to ensure that adolescents safely navigate the transition from childhood to adulthood — from the car seat to the driver’s seat.”

CIRP experts have spent many hours dissecting the factors behind why teens crash and what skills new drivers are missing. They compiled research and evidence-based practice about the major constructs around safe driving behavior. Team members also mined a massive database called the National Motor Vehicle Crash Causation Survey, and they identified the most common crash scenarios involving teen drivers.

Their work has led to the innovative concept of developing a systematic method for diagnosing driving skill level as a crucial step in personalized driving management plans. The first phase of their work is nearly complete: The team has built and validated an initial version of a Simulated Driving Assessment (SDA) tool that uses a high fidelity driving simulator located at CIRP to achieve realistic reproductions of driving experiences and conditions.

Study participants are exposed to a series of “drives” that involve variations of three main crash scenarios during a 35- to 40-minute session. The researchers collect and analyze data on numerous aspects of the drivers’ performance — from steering and braking reaction times to eye movement and headway time — and can produce an automated report.

“Some teens may have trouble with attention; some may have trouble with hand-eye coordination; some may not have the cognitive skills needed to drive safely; and due to inexperience, most have skill deficits,” Dr. Winston said. “By diagnosing driving, we want to tease out what driving deficits a teen might have before he or she crashes.”

Having a mechanism in place that gives clinicians and parents a better sense of whether or not teens are ready for independent driving is especially important in states like Pennsylvania that have laws requiring physicians to medically certify that a patient is fit to drive. If a teen has some type of medical condition that could impair his or her ability to safely operate a motor vehicle, physicians are mandated to report it to the Pennsylvania Department of Transportation.

As the CIRP team gains more experience at determining which teens could benefit the most from the SDA, Dr. Winston’s future dream is to establish a driving clinic at CHOP. Physicians could refer patients to the clinic for screening, and based on the driving diagnosis, young drivers would receive recommendations or training to help improve their performance on the road. Already, the CIRP team has published findings that show novice drivers benefit from web-based training programs that expand the diversity of the teens’ driving practice.

“CHOP is at the forefront of teen driver safety research, and it is an amazing place to take these leaps because of our interdisciplinary nature,” Dr. Winston said. “Generous funding from the Pennsylvania Department of Health allowed us to get the driving simulator and put us in a unique position to address the leading cause of death for teens.”

The CIRP team is encouraged by interest from other potential partners who support this urgently needed line of research and are looking for sponsorship to making a driving clinic at CHOP a reality.

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Discovering, Optimizing Epilepsy Therapies with Genetics


A new study led by The Children’s Hospital of Philadelphia’s David Bearden, MD, and Ethan M. Goldberg, MD, PhD, supports the idea that the identification of specific genetic targets could lead to a sea change in the way epilepsy is treated. Published in the Annals of Neurology, the paper reports the case study of one young patient with migrating partial seizures of infancy (MPSI) who was successfully treated with a drug originally intended for cardiac patients.

A rare, severe form of epilepsy that generally presents in the first few months of life, MPSI is characterized by frequent, treatment-resistant seizures, resulting in developmental delays and disabilities, and often leads to death in childhood. Drs. Bearden and Goldberg’s study is a close look at the effect the antiarrhythmic drug quinidine had on the patient’s seizures.

So why use a cardiac drug (and one used to treat malaria) to treat epilepsy? Because MPSI is generally resistant to anticonvulsant drugs, the researchers decided to look elsewhere for ways to treat the disease. “MPSI is associated with mutations in a variety of genes,” the authors note, one of which is the potassium channel KCNT1. This gene, the authors point out, is activated in MPSI, and is “a known target of several cardiac drugs, including the antiarrhythmic drug quinidine, which operates as a pore blocker.” Therefore, the study team notes, inhibition of KCNT1 might be a way to treat MPSI by normalizing potassium current through mutated KCNT1 channels.

When the study team first saw the patient at age two, she was experiencing between five and 20 seizures a day. By the end her of treatment — comprising some 210 days — the patient had been completely seizure-free for more than four months, and mostly seizure-free (save for during illness, and when her dosage needed to be adjusted) for more than 90 percent of her treatment time. Encouragingly, the patient showed developmental improvements during this time, hitting several major milestones — saying her first words, and then her first sentences.

This “dramatic reduction in seizure frequency” seen during the patient’s treatment shows quinidine “may be at least partially effective in the treatment of MPSI associated with activating KCNT1 mutations,” the study team notes. And overall, the authors say their case “is illustrative of a new paradigm in epilepsy treatment in which rapid identification of genetic mutations could lead to targeted treatments with greater efficacy and fewer side effects than is possible with currently available antiepileptic drugs.”

Indeed, in an accompanying commentary, Boston Children’s Annapurna Poduri, MD, MPH, writes that Drs. Bearden and Goldberg’s study “is an elegant illustration of the potential for genetic diagnosis in epilepsy to influence treatment and to lead to specific, targeted treatment.”

“The promise of precision medicine offers hope for many patients with epilepsy, and it is patients with refractory epilepsies like MPSI who most urgently need this kind of paradigm-changing approach to treatment,” she notes.

To learn more about epilepsy research and treatment at CHOP, see Children’s Hospital’s Pediatric Regional Epilepsy Program, part of the Division of Neurology.

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Intervention Aims to Promote Effective Practice for ADHD


Approximately 7,800 children with attention-deficit/hyperactivity disorder (ADHD) visit primary care practices across The Children’s Hospital of Philadelphia Care Network. Treating such a large patient population that is coping with a multifaceted, chronic condition can be demanding for busy primary care physicians (PCPs). That is why a study team at CHOP is launching an outcomes improvement project in the fall to promote PCPs’ use of clinical practice guidelines for managing ADHD consistently and efficiently.

ADHD is the most common neurobehavioral disorder among children, occurring in about 8 percent of youth. Yet each child experiences symptoms of inattention, impulsivity, and hyperactivity differently, so delivering treatment that is responsive to individuals’ specific needs, goals, and family preferences can be time-consuming and complex.

The major features of treatment for children with ADHD include parental support and education in behavioral training, appropriate school placement, and medication. Subsequently, the ADHD care team goes beyond the pediatrician office’s walls and extends to families, teachers, guidance counselors, coaches, social workers, and other healthcare providers including psychologists, psychiatrists, and neurologists.

“ADHD is somewhat more difficult to manage than some other conditions in the sense that many of the problems show up at school and home, so it takes care coordination across different settings,” said Alexander G. Fiks, MD, MSCE, associate medical director of the Pediatric Research Consortium (PeRC), and associate director for Outpatient Research Activities, Center for Pediatric Clinical Effectiveness (CPCE) at CHOP. “It is hard to keep engaged with multiple healthcare providers, schools, and families and easily exchange information.”

For children who are prescribed medications for ADHD, Dr. Fiks added, it may take a few months to achieve optimal success, and the guidelines recommend that medication efficacy should be systematically monitored at regular intervals. It can be cumbersome to schedule and accomplish those follow-ups from an organizational standpoint.

Even with these challenges, keeping ADHD management on track is crucial, Dr. Fiks said, because early detection and intervention can reduce the severity of symptoms, decrease the interference with school functioning, enhance the child’ self-esteem and social relationships, and improve the quality of life experienced by children or adolescents with ADHD and their families.

The study team’s project aims to give PCPs the tools they need to initiate and sustain appropriate treatments and achieve successful long-term outcomes. In preparation for the project, a set of practice supports will be built into a web-based portal linked to CHOP’s electronic health record to promote shared decision-making. Practitioners also will be offered the option of obtaining American Board of Pediatrics Maintence of Certification Part IV credit through their participation.

Overall, the intervention will include an integrated approach featuring:

The investigators will conduct a randomized controlled clinical trial to evaluate the effectiveness of the intervention over eight months to increase the use of evidence-based practices among PCPs for children with ADHD. They will contact providers in CHOP’s 31 primary care practices to inform them of the study, which focuses on patients in the age range from 5 to 12 years.

Providers in the control group will be given brief education about how to use the portal, while the experimental group will receive detailed guidance about the portal along with the multiple components of the integrated approach. The study team already has formed an advisory board that consists of parents, clinicians, and teachers from throughout the communities that CHOP’s Care Network serves.

“We predict that if clinicians have more knowledge and backup support, then they will feel more confident in the recommendations that they have for families,” Dr. Fiks said. “Introducing the EHR technology as a way to facilitate information exchange also will make ongoing communication easier. And by giving feedback, clinicians will see their strengths and weaknesses, in order to help improve the care that they deliver.”

The project is a collaborative effort that taps the talents of several CHOP experts including co-principal investigator Thomas J. Power, PhD, director of the Center for Management of ADHD; co-investigator Nathan J. Blum, MD, acting associate chief of the Division of Child Development, Rehabilitation Medicine and Metabolic Disease; co-investigator James Guevara, MD, MPH, attending physician; collaborator Robert Grundmeier, MD, attending physician; and other team members from the Center for Biomedical Informatics, PolicyLab, CPCE, and PERC. It is funded by an unrestricted, independent research grant from Pfizer.

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Healthy Weight Program Launches Study on Microbiome


Trillions of naturally occurring bacteria and other microbes coexist in the human gut and are part of how we process food and harness energy. Known as the microbiome, this complex collection’s potential role in early weight gain and obesity has become a fascinating area of scientific exploration.

Approximately 10 percent of children in the U.S. are already obese by age 2. These rates are especially concerning because research suggests that infants with rapid growth during the first two years of life may be more likely to be obese later in childhood and into adulthood. Excessive weight gain in childhood is associated with elevated blood pressure, musculoskeletal complaints, and asthma.

An interdisciplinary study team from The Children’s Hospital of Philadelphia’s and University of Pennsylvania has begun an observational cohort study that will focus on the role of the gut microbiome in the development of obesity early in life. It is a unique research opportunity because babies are born with close to sterile conditions, but they are quickly colonized with the microbes that they are exposed to in their environment.

“We are enrolling moms during their third trimester and trying to characterize their vaginal and gut microbiota, look at the transmission to infants, and follow the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain,” said Babette S. Zemel, PhD, principal investigator of the Infant Growth and Microbiome (I-gram) study. “We are focusing on low-income African American families because they have the highest rates of obesity in adulthood in the U.S. We want to try to tackle this problem early if we can.”

Not only will the researchers consider the microbiome in this long-term study, but they also will have the opportunity to simultaneously investigate a number of other risk factors associated with obesity. For example, epidemiological evidence suggests that children born by cesarean section have higher rates of obesity than those who are born vaginally. This points to the hypothesis that infants who miss out on early transmission of maternal microbiota could be more susceptible to excess weight gain in childhood.

In a subset of babies, the researchers plan to observe how rapidly the infants’ microbial communities cultivate. For another subset, they intend to track any babies who are prescribed antibiotics, in order to identify fluctuations in the microbial profiles after the infants receive the medications and to see how quickly the microbes are restored.

“Fluctuations in microbial profiles could support a mechanism for the association between antibiotics and early obesity,” said Patricia DeRusso, MD, MS, director of the Healthy Weight Program at The Children’s Hospital of Philadelphia.

A recent Healthy Weight Program-funded study using electronic health records explored the potential association between repeated exposure to broad spectrum antibiotics in early ages and childhood obesity. L. Charles Bailey, MD, PhD, is the principal investigator of the study, and the results were published online Sept. 29 in JAMA Pediatrics.

An additional focus of the I-gram study will be to examine the role of multiple feeding-related factors including breastfeeding, formula feeding, sucking behavior, feeding patterns, and timing of introduction of solid foods.

Looking at the potential interaction of these novel mechanisms will help to create a detailed description of what happens in the first year of life among infants born to 300 normal weight vs. obese African American, predominantly low-income mothers. The moms will give birth at the University of Pennsylvania where study collaborators will collect samples at the time of delivery. Next, infant growth experts at CHOP will measure the infants and follow their development carefully over the next 12 months. They will use a machine called a Pea Pod to periodically measure the infants’ body composition — the amount of fat and lean tissue in the body.

“The long-term implication of this study is that if we can identify early predictors of weight gain during infancy, it is an ideal opportunity to intervene in some way,” Dr. Zemel said.

Interest in the microbiome has flourished as better tools have emerged that allow scientists to analyze the microbes’ DNA and their metabolic byproducts, which are an essential part of our digestive system. Intriguing research suggests that people who are obese have a different profile of microbiota than people who are not obese. Dr. Zemel pointed out that findings from a study of twins, in which one twin was obese and the other was not, demonstrated that a fecal microbiota transplant from the obese twin into germfree mice resulted in weight gain for the rodents.

“This adds to the evidence that there is some causal link between the gut microbiome and the development of obesity,” Dr. Zemel said.

The I-gram study is one of 10 research projects in the portfolio of CHOP’s Healthy Weight Program that aim to advance understanding of the root causes of obesity and effective models for prevention and treatment, focused on early childhood intervention.  Funding was provided by an unrestricted donation from the American Beverage Foundation for a Healthy America to The Children’s Hospital of Philadelphia to support the Healthy Weight Program.

“Obesity prevention is a signature area of our research,” said Gurpreet Kalra, MS, CCRP, research program manager for the Healthy Weight Program. “Our agenda is informed by the latest Institute of Medicine’s guidelines that stressed the lack of research on obesity prevention in very young children. Identification of novel, modifiable risk factors, which is the focus of the I-gram study, is key to obesity prevention.”

The portfolio has a comprehensive focus because obesity is a complex, multifactorial disease and uses a variety of electronic health records, social media, and community partnered strategies to conduct the research.

“We are committed to long-term studies that can more conclusively prove causality and test the effectiveness of interventions,” Gurpreet said.

Most of the studies involve children and families from neighboring high-risk populations and communities where obesity rates are among the highest in the city. The multidisciplinary investigative team includes experts in anthropology, pediatric and adult gastroenterology, endocrinology, psychology, psychiatry, obstetrics and gynecology, microbiology, genetics, public health, and biostatistics.

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Report Supports Prenatal Spina Bifida Surgery as Standard of Care


Reporting on 100 recent cases of fetal surgery for spina bifida, specialists from The Children’s Hospital of Philadelphia achieved results similar to those in a landmark clinical trial that established a new standard of care for prenatal repair of this birth defect.

The single-center study from the Center for Fetal Diagnosis and Treatment at CHOP represents the largest series reported since 2011 when the National Institutes of Health-sponsored Management of Myelomeningocele Study (MOMS) published its results in the New England Journal of Medicine.

Three years ago, the MOMS showed that fetal surgery led to decreased rates of shunting, which involves implanting a tube to drain excess fluid from the brain, at 12 months of age. Fetal surgery also reversed a life-threatening condition called Arnold Chiari 2 malformation, otherwise known as hindbrain herniation, and improved the children’s outcomes, including their ability to walk at 30 months of age.

“The MOMS trial presented very encouraging results and helped experts develop guidelines for optimal care, but there were questions about whether the benefits of this procedure could be reproduced outside the setting of a rigorous trial,” said Julie S. Moldenhauer, MD, a maternal-fetal medicine specialist at CHOP and lead author of the current paper in the journal Fetal Diagnosis and Therapy. “This study shows that an experienced program can achieve comparable results, and that we can modify our techniques to improve on the trial outcomes.”

CHOP’s center was one of the three fetal surgery programs that participated in the randomized MOMS trial, and has been performing fetal myelomeningocele (fMMC) repairs since 1998. In total, CHOP has performed more than 1,175 fetal surgeries for a range of birth defects, the largest number of any hospital in the world.

The current study draws on a cohort from all patients referred to CHOP for potential fMMC repair between January 2011 and March 2014. Of 587 total referrals, the program designated 139 to be candidates for the fetal surgery, and 100 mothers completed the surgery.

The current cohort had a decreased incidence of preterm premature rupture of membranes (PPROM) compared to the MOMS group; average operative times were significantly shorter; there were decreases in the incidence of pulmonary edema and the transfusion rate at the time of cesarean delivery. Also, early neonatal MRIs showed that 71 percent of the infants had no evidence of hindbrain herniation, in which part of the cerebellum (hindbrain) protrudes through the opening in the base of the skull into the spinal canal and obstructs the flow of cerebrospinal fluid, leading to a progressive hydrocephalus.

In addition, when compared to prenatal ultrasound evaluations of the anatomic level of the myelomeningocele, 55 percent of the newborns in the study had improved functional motor level, but the authors added that follow-up research will be needed to determine if this benefit persists in longer-term outcome studies.

For more details on the study, click here.

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Researchers Discover Gene Mutation in Blood Disorder


An international team of scientists has identified a gene mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which three generations had blood disorders, the researchers discovered a defect in a gene that regulates telomeres, chromosomal structures with crucial roles in normal cell function.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said the study’s co-leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. Dr. Hakonarson and a number of other CHOP investigators collaborated with Australian scientists on the study, published recently in the journal Blood.

“We’re thrilled by this discovery which has advanced our understanding of certain gene mutations and the causal relationship to specific diseases,” said the study’s co-leader Tracy Bryan, PhD, from the Children’s Medical Research Institute in Westmead, New South Wales, Australia.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. The investigators performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.Telomeres, complex structures made of DNA and protein, are located on the end of chromosomes, where they protect the chromosomes’ stability. They are sometimes compared to plastic tips at the end of shoelaces.

Telomeres shorten after each cell division, and gradually lose their protective function. Aging cells, with their shortened telomeres, become progressively more vulnerable to DNA damage and cell death. Separately from the aging process, certain inherited and acquired disorders may shorten telomeres and injure rapidly dividing blood-forming cells produced in bone marrow. This leads to bone marrow failure, one example of which is aplastic anemia.

Dr. Bryan’s team investigated the function of the ACD gene. They determined that the mutation shortened telomeres and interrupted the ability of telomeres to attract the enzyme telomerase, which counteracts telomere shortening and thus protects cells.

The researchers showed that the mutation in ACD alters the telomere-binding protein TPP1, disrupting the interactions between telomere and telomerase. Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list, the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” said Dr. Hakonarson. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

To read more about the innovative work being done at the Center for Applied Genomics, see the Center’s website.

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Genetic Study Gives Clues to Intellectual Abilities


As students with bulging backpacks return to school this fall, each one also brings a unique skill set to the classroom. One child may be a math whiz, while their buddy in the next desk is an avid reader. A large genetic study conducted by experts at The Children’s Hospital of Philadelphia and University of Pennsylvania’s Perelman School of Medicine may lead to new ways to evaluate these complex traits in children’s intelligence.

The study drew on the largest data set ever used in a single sample across multiple cognitive traits grouped within five broad domains: executive function, memory, complex cognition, social cognition, and reading ability. Previous estimates of the heritability of cognitive traits relied on much smaller twin and family studies; however, the authors note that their current research represents a first step in discerning the overall genetic architecture of cognitive abilities.

The researchers performed genotypes of all participants, administered a battery of neurocognitive tests, and assessed participants in structured psychiatric interviews. They used a powerful gene software tool called genomewide complex trait analysis (GCTA) to analyze a subset of 3,689 individuals aged 8 to 21, all of European ancestry, drawn from the Philadelphia Neurodevelopmental Cohort, a general-population sample of close to 10,000 individuals who received care within CHOP’s pediatric network for a broad range of health needs.

The GCTA analyzes common SNPs (single-nucleotide polymorphisms, changes of a single base in DNA) to estimate how much these common gene variants contribute to differences in cognitive abilities within the total sample.

“When we computed the contribution of common variants to these cognitive abilities, we found that some of the contributions were substantial,” said one of the study’s two co-senior leaders, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia.

For instance, common SNPs accounted for roughly 40 percent of the population differences in nonverbal reasoning, and 30 percent of the differences in language reasoning, with the balance of the differences attributable to rare variants and environmental factors. On the other hand, common gene variants together contributed to only 3 percent of the differences in spatial memory — the ability to navigate in a geographical location. The researchers also identified significant overlaps between trait domains. Reading ability, which was 43 percent attributable to common variants, was often inherited together with language reasoning abilities.

“Intuitively, it makes sense that skills in reading and language reasoning are related,” said Dr. Hakonarson, who added that those traits might be investigated together in future genetic and neurobiological studies.

Upcoming research also will focus on analyzing age-dependent differences to investigate how genetic influences vary as children mature. Other, larger studies should focus on non-European populations. Ultimately,  Dr. Hakonarson added, if the current findings are replicated and extended, researchers may be able to generate a genetic profile reflecting a normal distribution of cognitive abilities.

“Uncovering the genetic architecture of these diverse cognitive abilities may offer new insights into cognitive development and may ultimately allow investigators to identify useful biomarkers for diagnosing and predicting risks of neuropsychiatric conditions,” Dr. Hakonarson said.

The study appeared online July 15 in Molecular Psychiatry. Dr. Hakonarson’s co-senior author is psychiatrist Raquel Gur, MD, PhD, director of Neuropsychiatry in the Perelman School of Medicine at the University of Pennsylvania. The study team represents a collaboration among the CHOP and Penn investigators with colleagues at the Broad Institute, Harvard Medical School, and Massachusetts General Hospital who developed GCTA.

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Gene-regulating Protein Reaches Multiple Disease Pathways


Genomic scientists at The Children’s Hospital of Philadelphia recently found strong evidence that the protein family FOXA2 is a master regulator of genetically vulnerable pathways in multiple diseases.

Study leader Struan F.A. Grant, PhD, holder of the Daniel B. Burke Chair for Diabetes Research at The Children’s Hospital of Philadelphia, has long investigated the genetics of diabetes and obesity. In the current study, he focused on the Forkhead Box A transcription factor, referred to as FOXA2, which was already known to act in the liver in affecting glucose levels. Dr. Grant and colleagues started with the hypothesis that FOXA2 regulated molecular pathways that are important in endocrine biology.

As they performed their analyses, the researchers found that FOXA2 proteins acted on sites in the genome that contained genes affecting endocrine-related traits such as glycemic levels, although not type 2 diabetes. They also found strong genome occupancy patterns associated with cardiovascular traits such as lipid levels, as well as with neuropsychiatric traits and cancer.

“FOXA2 appears to function as a master regulator for over a hundred other transcription factors, so it may play an outsized role in human health and disease,” Dr. Grant said.

This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and used two important tools of next-generation genomic analysis: chromatin immunoprecipitation and massively parallel sequencing, together abbreviated as ChIP-seq. ChIP-seq isolates the pieces of DNA that are bound by proteins such as transcription factors.

Researchers then pass those fragments through automated sequencing machines to pinpoint and inventory the regions of the genome that specific transcription factors occupy. This knowledge allows investigators to better understand how transcription factors may activate or repress genes along important biological networks, and further study of those pathways may point the way to various novel therapies.

Dr. Grant and colleagues published their study in the The Journal of Clinical Endocrinology & Metabolism.

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Scholar Hope Grant Supports Neuroblastoma Research


Pediatric oncology researchers at The Children’s Hospital of Philadelphia are driven to find new treatments for childhood cancer, and the Hyundai Hope On Wheels program is supporting their hard work by awarding a 2014 Scholar Hope grant to help fund investigations that focus on the aggressive form of neuroblastoma. Despite intense treatment, more than 50 percent of children with high-risk neuroblastoma die of their disease, accounting for 12 percent of pediatric cancer deaths.

Kristina Cole, MD, PhD, an attending physician and researcher with expertise in identifying therapeutic targets in pediatric cancer, received the Scholar Hope grant at a “Handprint Ceremony” in front of the hospital Sept. 11. Children from the oncology floor were invited to place their handprints in paint on a Hyundai car that is traveling across the country to build awareness of pediatric cancer research. Hyundai Motor America and its more than 820 U.S. Hyundai dealers have donated more than $86 million to pediatric cancer research in the U.S. through Hope On Wheels.

Each child’s handprint stands out as one of a kind, as does Dr. Cole’s novel research project which aims to demonstrate, for the first time, that a subset of patients with neuroblastoma could benefit from checkpoint inhibition and support further clinical development of new generation checkpoint inhibitors for pediatric solid tumors.

In previous work, Dr. Cole and colleagues have shown that neuroblastoma tumors rely on the DNA repair checkpoint protein kinase 1 (CHK1) to handle the cellular stress caused by the powerful MYCN oncogene that drives tumor growth. When CHK1 is inhibited, the neuroblastoma cells can no longer grow and die. Several clinical trials are underway based on the idea that if cancer cells are exposed to a CHK1 inhibitor, the protein will be unable to respond when the cell’s DNA is damaged by treatments such as chemotherapy.

“This current research is unique because we’re trying to better understand which patients may benefit and why they may benefit,” Dr. Cole said. “We think that MYCN certainly has a very large role, but is it possible that other factors — like underlying defects in genes that mediate DNA damage — make certain patients even more likely to benefit from this treatment strategy.”

First, researchers will analyze large genomic datasets from hundreds of primary tumor samples to find any defects in DNA repair genes. Then, they will characterize how those mutations could make neuroblastoma tumors more sensitive than other tumor types to drugs that inhibit CHK1. Their third aim will be to do preclinical work in the laboratory with cell cultures and animal models to be able to justify a clinical trial of next generation checkpoint inhibitors in combination with traditional chemotherapy.

The researchers’ hypothesis that certain neuroblastoma tumors have increased dependency on the compensatory DNA repair pathway due to a possible defect in DNA repair genes is reminiscent of what has been described in breast cancer research, Dr. Cole said. Breast tumor cells with inherent DNA repair defects, such as mutations in BRCA1 or BRCA2, are sensitive to drugs that inhibit PARP, another protein that helps cancer cells repair DNA damage and survive. Tumor cells with normal BRCA proteins continue to grow.

Dr. Cole is among 36 Scholar Hope two-year grant winners, who each received $250,000 for a total of $9 million in support. The ultimate goal of the Scholar Hope grant program is to find cures for childhood cancers once and for all, according to the program’s website.

“It is a great award that they’ve put together to support the work done by individuals from Children’s Oncology Group institutions all across the country who are investigating pediatric cancers,” Dr. Cole said. “They’ve been very generous to CHOP.”

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Research Institute Leader Named to Brain Tumor Foundation Panel


The Children’s Hospital of Philadelphia Research Institute’s Tom Curran, PhD, FRS, was recently named to a panel of experts who will advise the Pediatric Brain Tumor Foundation (PBTF). A pediatric brain tumor expert and Deputy Scientific Director of the Research Institute, Dr. Curran was one of seventeen volunteers appointed to the PBTF’s newly created Research Advisory Network.

Per a statement put out by the PBTF, the “Research Advisory Network will contribute insights that help shape the PBTF’s funding priorities and evaluate the impact of its research investment on the lives of children diagnosed with a brain tumor, as well as on the disease that threatens them.” Panel members come from several other children’s hospitals—including St. Jude’s, Boston Children’s, and Children’s National—as well as academic centers and industry.

“The members of the Research Advisory Network, or RAN, will provide highly informed perspectives on the biomedical research enterprise,” said the PBTF’s Dr. Joanne Salcido. According to its website, the PBTF is “the world’s largest nonprofit funder of childhood brain tumor research,” and in addition to funding studies the Foundation hosts events, offers brain tumor-related resources, and offers scholarships.

Before joining Children’s Hospital in 2006, Dr. Curran was the founding chairman of the Department of Developmental Biology at St. Jude’s Research Hospital in Memphis, Tenn. In addition to his role as deputy scientific director of CHOP Research, Dr. Curran is also a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

He is also one of the leaders of the recently established Children’s Brain Tissue Tumor Consortium (CBTTC). A multi-institutional, collaborative research organization dedicated to the collection, annotation, and analysis of children’s brain tumors, the CBTTC’s ultimate goal is to improve outcomes for children with brain tumors. The CBTTC is comprised of CHOP, the Children’s Hospital of Pittsburgh of UPMC, Seattle Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago. The consortium’s operations center is housed at Children’s Hospital.

“I am honored to serve as a member of the Pediatric Brain Tumor Foundation’s Research Advisory Network,” Dr. Curran said. “I look forward to working with the Foundation, as well as my fellow Network members, to advance brain tumor research and improve the lives of children with brain tumors.”

To learn more about brain tumors and cancer care at The Children’s Hospital of Philadelphia, see the Cancer Center at CHOP. For more information about cancer research at CHOP, see the Center for Childhood Cancer Research.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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