Bench to Bedside

April 2014

Going With the Gut to Build Preterm Infants’ Immunity


At birth, infants move from a sterile environment to one full of microorganisms. They rapidly acquire alterations in their immune systems that help them to survive in this dirty world. Researchers at The Children’s Hospital of Philadelphia used mouse models to show that changes in microbial colonization of the gastrointestinal tract play a vital role in this transition.

Their findings, recently published in Nature Medicine, offer a possible explanation as to why human premature infants are more vulnerable to serious infections. Ultimately, this research may lead to potential treatments to restore critically ill newborns’ resistance to common pathogens, such as E. coli., in the neonatal intensive care unit. One out of every eight babies is born premature each year in the U.S., according to the Centers for Disease Control and Infection.

“Babies who are born preterm, in addition to them having less ability to fight infection, are more likely to get infected, either as a consequence of being born premature or exposure to microbes from the mother’s womb,” said Hitesh Deshmukh, MD, PhD, of CHOP’s division of neonatology and department of pediatrics, who co-authored the study.

Human babies experience a burst of production of infection-fighting white blood cells within 12 to 24 hours after birth, a process known as granulocytosis. The investigators demonstrated that neonatal mice had the same spike in white blood cells; however, this acceleration was diminished in mice that had been exposed to antibiotics, which contributed to increased susceptibility to E. coli K1 sepsis, a severe blood infection.

“Usually a low white count is a harbinger of bad things,” Dr. Deshmukh said. “It means that your body does not have enough white cells to fight an infection, and you’re more likely to be sicker.”

Neonatologists frequently prescribe antibiotics in NICUs because signs of infection in preterm babies are difficult to decipher, Dr. Deshmukh said. Yet, counterintuitively, recent research shows that prolonged antibiotic use in preterm babies can give rise to late-onset sepsis.

The Nature Medicine study suggests a mechanism that explains why preterm babies exposed to antibiotics, either directly or through their mother, tend to get sicker. Perhaps antibiotics hamper their natural buildup of granulocytes, as described in the mice models, which makes the preterm babies more prone to infection and less able to resist sepsis.

Study co-author G. Scott Worthen, MD, a professor of pediatrics in the Division of Neonatology at the Perelman School of Medicine at the University of Pennsylvania, emphasized that researchers do not know definitively how closely newborn mice resemble preterm human babies from an immunological perspective, so this study cannot be applied directly to humans. But the results point to a fascinating pathway for investigation that could offer new interventions.

The CHOP researchers found that regulation of postnatal granulocytosis likely lies within the gut microbiome. By adulthood, a community of a hundred trillion microbes form along a person’s gastrointestinal tract, but at birth, the gut is sterile. Microbial colonization of the gut starts upon an infant’s arrival into the world, initiating an immune response. “When you interrupt this pattern of colonization, either by giving antibiotics or some other mechanism, you make the babies more susceptible to infection,” Dr. Deshmukh suggested.

A prevailing thought is that antibiotics act on the bone marrow and decrease its ability to produce white blood cells, but Dr. Deshmukh and his team showed that this is not the case. They demonstrated that germ-free mice, which are born in sterile environments and are not naturally colonized with microbiota, behaved similarly to the mice that were exposed to antibiotics.

“While some antibiotics may affect the bone marrow directly, we believe these effects are due to the influence of antibiotics on bacteria in the gut,” Dr. Deshmukh said. “If you were to replace some of those microbes, you might restore the resistance of the newborn to the infection.”

His research team proved this by taking normal intestinal microbiota from mice that were not exposed to antibiotics and transferring them to mice that had received antibiotics. In adult humans, this procedure is called a fecal transplant, which is highly effective at eradicating C. difficile infection. “Fecal transplant could be one of the ways in which you could make sure that babies have more resistance or more power to fight infection,” Dr. Worthen said.

But he cautioned that substantial research and safety testing must be done to determine which groups of microbes potentially are beneficial for preterm infants. Once researchers pinpoint the good and bad bugs, they could isolate, purify, and manipulate certain bacterial components that could trigger postnatal granulocytosis.

“One of the things you could do with this mixture is to use it to rapidly reconstitute an infant after they’ve finished a course of antibiotics,” Dr. Worthen said. “We still have to give antibiotics, but what happens after you stop? The infants get colonized with the germs that are in the NICU. That’s a horrible combination of events.”

Dr. Deshmukh and his team will focus their future research on identifying bacterial components that could generate a new microbial community for preterm infants’ who needed antibiotics and subsequently preserve or restore their resistance to infection.

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Study Will Compare Broad, Narrow-Spectrum Antibiotics


The Children’s Hospital of Philadelphia’s Jeffrey S. Gerber, MD, PhD, recently received an approximately $1.8 million contract from the Patient-Centered Outcomes Research Institute (PCORI) to compare the effectiveness of broad and narrow-spectrum antibiotics in treating acute respiratory infections. An infectious diseases specialist and a Center for Pediatric Clinical Effectiveness (CPCE) faculty member, Dr. Gerber investigates the epidemiology and outcomes of antibiotic use in children.

PCORI was established by the Affordable Care Act to fund and carry out comparative effectiveness research. Last year PCORI awarded the CPCE’s Ron Keren, MD, MPH, more than $2 million to study the effectiveness of oral and intravenous antibiotics. Since PCORI began funding research projects in 2012, the organization has awarded a staggering $464 million to support 279 projects. Dr. Gerber’s award was one of 71 announced during the fourth quarter of 2013.

Dr. Gerber’s three-year investigation will be focused on the use of antibiotics to treat acute respiratory tract infections (ARTI), such as ear and sinus infections. Despite the fact that guidelines frequently recommend clinicians use narrow-spectrum antibiotics to treat ARTI, many doctors often prescribe broad-spectrum antibiotics.

According to a 2011 Pediatrics study led by the University of Utah’s Adam L. Hersh, MD, PhD, between 2006 and 2008 there were approximately 65.6 million doctor’s visits for respiratory conditions, comprising 29.9 million visits for ARTI for which antibiotics are indicated, 19.5 million visits for ARTI for which antibiotics are not indicated, and 16.2 million for other “respiratory conditions for which antibiotics are not definitely indicated.”

During those 65.6 million visits, there were 31.7 million antibiotic prescriptions made (or during 48.4 percent of visits), including 5.8 million prescriptions to treat ARTI for which antibiotics are not indicated. Overall, broad-spectrum antibiotics were prescribed more than half the time. Dr. Gerber said roughly 80 percent of outpatient pediatric antibiotic prescriptions are intended to treat four conditions: ear infections, strep throat, sinus infections, and pneumonia.

While prescribing antibiotics can be challenging for general practitioners because there are so many different types of drugs — and within those types different classes, as well as new drugs being approved all of the time — “guidelines for antibiotic prescribing for the most common conditions that affect kids are relatively straightforward,” Dr. Gerber said. For example, the CDC’s prescription guidelines for pharyngitis recommend using a penicillin (a narrow-spectrum drug) to treat group A strep, reserving broader-spectrum agents for patients allergic to penicillin.

Because pediatric antibiotic prescription rates have been documented, with this project Dr. Gerber and his team will seek to learn more about the safety and efficacy of those drugs. “Using parent- and patient-centered outcomes, this study is designed to identity which antibiotic choices best optimize clinical outcomes while minimizing side effects,” said Dr. Gerber.

Using Qualitative Research to Inform Quantitative Research

Dr. Gerber’s project will be conducted in two parts: first the researchers will conduct in-person qualitative interviews with parents and children who visit the pediatrician’s office with ARTI symptoms. The goal of this interview study is to allow parents and children to express, in their own words, the outcomes related to antibiotics that are most important to them. The investigators will then use the data gleaned from these interviews to generate outcomes that will be assessed the study’s second arm.

To oversee the interviews, Dr. Gerber has teamed with a medical sociologist, Julia Szymczak, PhD. Dr. Szymczak, a postdoctoral fellow in the Division of Infectious Diseases, designed the interviews to “help generate outcomes that can then be tested quantitatively,” she said. The strength of qualitative research “lies in its open-endedness and ability to generate insights that you hadn’t previously considered.” This first arm of the study is already underway, and the researchers are ultimately looking to recruit 100 parents and children across the CHOP network.

In the second half of the project — tentatively scheduled to begin in the fall — the researchers will conduct phone interviews with a much larger patient population, approximately 3000 families. They will follow the patients prospectively, calling 10 and 30 days following an antibiotic prescription. In addition to assessing traditional medical outcomes, the investigators are seeking to gauge “outcomes that aren’t typically on a medical chart” — like diarrhea, sleeplessness, absence from school, and missed days of work, which may not require a visit to the hospital but can be disruptive for patients and families, Dr. Gerber said.

 Project’s Possible Implications

The possible implications of the project are wide-ranging, as antibiotic prescribing, and ARTI, are so widespread. “This project was selected for PCORI funding not only for its scientific merit but also for its potential to fill an important gap in our health knowledge and ultimately help patients and those who care for them make more fully informed decisions about their care,” said PCORI Executive Director Joe Selby, MD, MPH.

There are a number of side effects and adverse events associated with antibiotic use. Side effects associated with penicillin, for instance, include upset stomach and diarrhea, and in serious cases rash, fever, and facial swelling. Erythromycin is also associated with upset stomach and diarrhea, as well as vomiting, stomach cramps, and mild skin rash. In rare cases it can cause hives, difficulty breathing, jaundice, and vaginal infections.

Additionally, there is a concern that overuse of antibiotics in general can lead to drug-resistant infections. Calling antibiotic resistance “a quickly growing, extremely dangerous health problem,” the CDC notes that each year in the U.S. “at least 2 million people become infected with bacteria that are resistant to antibiotics, and at least 23,000 people die each year as a direct result of these infections. Many more people die from other conditions that were complicated by an antibiotic-resistant infection.”

Dr. Gerber’s hope is that his project helps to empower families to ask the correct questions about their children’s care, and that it helps clinicians design better interventions.

“Given that these four conditions account for 80 percent of antibiotic prescribing, and given that outpatient antibiotic prescribing accounts for 80 percent of all antibiotic prescribing, even a small difference in efficacy can have huge implications,” Dr. Gerber said.

And for her part, Dr. Szymczak said the study is “a very comprehensive effort to be patient-centered,” adding that it is “exciting because it makes our science more relevant to people in the real world.”

In addition to Drs. Gerber and Szymczak, Children’s Hospital’s Theoklis Zaoutis, MD, MSCE, Alex Fiks, MD, and Louis M. Bell, MD, have all contributed to Dr. Gerber’s investigation.

To read more about Dr. Gerber’s project, see its PCORI page or the CPCE website.

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Advocates Shaky That NIH Funding Remains Steady


Advocates for biomedical research expressed their disappointment in President Barack Obama’s proposed budget for fiscal year 2015, which includes a slight rise in funding for the National Institutes of Health. This modest boost is expected to support 9,326 new and competing grants, 329 more than this year.

The FY15 budget in­cludes $30.2 billion for NIH to back research at institutions across the U.S. NIH Director Francis Collins, MD, PhD, told the Wall Street Journal that his agency is “grateful that in a tough budget year, the NIH was able to get an increase.” However, he noted that NIH is about $500 million behind where it was in the Obama administration’s proposed fiscal-year 2012 budget.

The research community had hoped that the 2015 budget would help to make up for lost ground following the devastating sequestration last year, which resulted in a 5 percent cut to NIH’s budget. Instead, they continue to worry that keeping funding levels at status quo will not sustain the fast pace of scientific innovation. Several research advocacy groups are calling on the administration and Congress to make a significant investment in NIH funding during their budget negotiations.

“The United States once stood firmly at the forefront of the research revolution, but after a decade of budgets that have not kept pace with inflation and last year’s across-the-board sequestration cuts, NIH has seen a more than 20 percent decline in its purchasing power and can only fund one in every seven research grants it receives,” wrote the United for Medical Research in a statement. “As such, the U.S. is slipping in its position as the global leader in the life sciences.”

The $30.2 billion proposed in the budget, adjusted for inflation, would be $100 million lower than the 2002 funding level for the NIH. Mary Woolley, president and CEO of Research!America, reiterated that insufficient funding levels for federal research and health agencies jeopardize scientific discovery and its capacity to improve health outcomes and stem the explosion of chronic diseases.

“We simply cannot sustain our nation’s research ecosystem, combat costly and deadly diseases like Alzheimer’s and cancer, and create quality jobs with anemic funding levels that threaten the health and prosperity of Americans,” Woolley wrote in a statement.

In his budget message, President Obama emphasized the importance of biomedical research and proposed an Opportunity, Growth, and Security Initiative that would provide an additional $970 million for NIH, which would support about 650 additional new grants. But an analysis of federal policy reported in Inside Higher Ed described this potential windfall as “almost fanciful” because the new initiative would depend on Congress reaching consensus on major changes in the tax code.

While The Science Coalition, a nonprofit, nonpartisan organization of the nation’s leading public and private research universities, appreciated the signs of President Obama’s “commitment to world-class science and research,” it remains wary about the long-term funding trends.

“The result is that we now face an innovation deficit — the gap between needed and actual federal investments in research and higher education,” stated Jon Pyatt, 2014 president of The Science Coalition. “We urge Congress to make investments in research and education a national priority. Only by doing so can we close the innovation deficit and truly put our nation back on a track for long-term economic health, well-being, and security.”

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Project to Investigate Cystic Fibrosis Drug’s Effect on Weight


A new project at The Children’s Hospital of Philadephia seeks to gain a clearer idea of what effect the novel cystic fibrosis (CF) drug ivacaftor has on energy balance and weight gain. With the support of the drug’s manufacturer, Vertex Pharmaceuticals, Children’s Hospital’s Virginia A. Stallings, MD, will measure the degree to which patients with CF taking ivacaftor — which is sold under the name Kalydeco — experience improvements in nutritional status and growth.

An inherited disease that is chronic, progressive, and often fatal, according to the Cystic Fibrosis Foundation CF affects approximately 30,000 adults and children in the United States and 70,000 worldwide. The disease is characterized by thick mucus that causes respiratory and digestive issues, and is associated with poor growth and weight gain, among other complications. There is currently no cure for CF, and until very recently most treatments have focused on alleviating the disease’s symptoms.

Kalydeco is approved to treat CF in patients 6 years of age and older who have specific mutations in their CF gene. Kalydeco was first approved in 2012 on the strength of trials that showed it improved lung function “and other aspects of CF such as increasing weight gain,” according to the FDA. “Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said the FDA’s Jane Woodcock, MD.

Though the FDA recently expanded the number of mutations for which Kalydeco is approved, because its approval only covers patients with particular mutations it can currently only treat a small segment of the overall CF population. Nonetheless, Kalydeco is a “breakthrough” drug, said CHOP’s Dr. Stallings.

Comprehensive, Investigator-Initiated Study

 With this project, Dr. Stallings will examine Kalydeco’s effect on CF patients’ energy balance and weight gain. A Professor of Pediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania’s Perelman School of Medicine, Dr. Stallings is a leading clinical nutrition and growth specialist.

The Kalydeco study is an investigator-initiated project that Dr. Stallings and her team proposed to Vertex after noting the unexpected weight gain observed during Kalydeco’s clinical trials, she said. Much of Dr. Stallings’ career has been spent working on ways to improve CF patients’ weight and growth, so the approval of Kalydeco — which treats the “primary cellular defect” — was “was a major, exciting, proof-of-principle,” she noted.

“What caught our eye with this is as they were doing the clinical trials there was a completely unexpected weight gain … almost every participant was gaining weight,” Dr. Stallings said.

She proposed a comprehensive study that will investigate what effect Kalydeco has on pancreatic function, how well patients are able to absorb food, and whether taking the drug has any effect on the patients’ appetite and food intake. Over the next 18 months, Dr. Stallings and her team will enroll patients who are about to go on the drug, so that they can measure the effect Kalydeco has on their weight, appetite, and energy intake and needs before, during, and after treatment. The study will make use of innovative “SmartPills” that can measure changes in pH and gastrointestinal motility, Dr. Stallings said.

In a related project supported by the Cystic Fibrosis Foundation, Children’s Hospital’s Andrea Kelly, MD, from the Division of Endocrinology and Diabetes, has been working on an investigation of Kalydeco’s effect on insulin and insulin secretion. If the investigators were able to compare findings (not to mention share study participants), “we would have a spectacular look at the whole metabolic change,” said Dr. Stallings.

Saying she was excited about the study, and the promise of novel therapies like Kalydeco, Dr. Stallings said, “we’ve never had a time in CF when we could almost guarantee weight gain … so here we have an experimental design where almost everybody is going to gain weight.”

To learn more about cystic fibrosis, and cystic fibrosis research at The Children’s Hospital of Philadelphia, see the Cystic Fibrosis Center website.

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Researchers Examine Goal Pursuit in Teens with Cancer


Setting and achieving goals is a significant milestone in adolescent and young adults’ (AYA) development that paves the way for independence in adulthood. Teens with cancer often experience fatigue, pain, and other symptoms that can interfere with these personal goals, something psychologists refer to as health-related hindrance (HRH).

Researchers at the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia are interested in identifying those most at risk for higher HRH because it is a potential marker of poor psychological adjustment during cancer treatment and into survivorship.  One of their studies that appeared in the March issue of the Journal of Clinical Psychology in Medical Settings focused on the interaction between race, ethnicity, and income in predicting HRH.

“This is one of the first studies to look at the psychosocial components of lower income and ethnic minority status on quality of life outcomes,” said Lauren C. Daniel, PhD, a psychology fellow in the Division of Oncology at CHOP.

Ninety-four study participants between the ages of 13 and 19 were categorized into four groups: lower income minority status, higher income minority status, lower income white, and higher income white. On average, it was 1.65 years since their initial diagnosis, and the majority had received chemotherapy.

The study participants wrote down up to 10 personally meaningful goals. Some examples included spending more time with friends and getting into a good college. Participants rated the difficulty and importance of the goal as well as the impact of pain, fatigue, and other symptoms on achieving each goal.

The research team examined differences in goal-related variables across the four groups, and their findings were not what they had anticipated. Based on previous research on health care disparities, they had hypothesized that adolescents with cancer of minority status living in lower income families would experience the highest amount of HRH. The results showed the opposite: Lower income minority patients had the least amount of HRH, while high income minority patients had the most.

“It may be that higher income minority families are in schools with higher expectations so patients may be more aware of the impediments that cancer poses,” Dr. Daniel said.

On the flip side, the researchers suggested that those adolescents with cancer in the lower income minority groups may rely on a “shift and persist” adaptive coping style that increases their resilience and persistence toward valued goals.

“This study highlights that goal setting may be different across patient populations,” Dr. Daniel said. “Their goals also might be different than what clinicians are expecting. So it’s important for them to talk with patients about things that they want to achieve, especially understanding how fatigue, pain, and symptoms impact their goals.”

During these conversations, clinicians can work with AYA to set realistic goals in the context of cancer to help motivate them to look toward the future. They also can connect them with organizations that offer information and support or scholarships and financial aid. At CHOP, many unique resources are available for AYA who are on and off treatment.

A larger scale study across multiple centers is needed to fully understand these preliminary findings and further explore the impact of sociodemographic factors on HRH.

“We’re hoping to work toward implementing interventions to improve health-related hindrance as an important part of quality of life of AYA with cancer,” Dr. Daniel said.

This study was part of a larger study on developmental outcomes of AYA with cancer by Lisa A. Schwartz, PhD, assistant professor of clinical psychology in pediatrics at CHOP and the psychologist for the Cancer Survivorship Program. Lamia P. Barakat, PhD, a CHOP psychologist, and Lauren D. Brumley, also contributed to the study.

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Pediatric Cancer Patients Need More Say in Phase 1 Trials


Children and adolescents with refractory cancer often are invited to participate in early phase clinical drug trials, but making the choice to enroll can be challenging for them and their families. A psychologist at The Children’s Hospital of Philadelphia explored how the extent and quality of communication with physicians, pediatric patients, and their parents may influence this difficult decision.

The study published in the Journal of Pediatric Hematology/Oncology is the first to observe actual informed consent conferences for pediatric phase 1 cancer research. Phase 1 trials are designed to determine the safety of novel agents and evaluate how often a new therapy should be given and at what dosage. During informed consent conferences, physicians provide details about the trial and discuss the patient’s and family’s willingness to participate.

An offer to join a phase 1 study is especially complicated for children with cancer because it typically marks a transition in their disease trajectory when there are no curative options remaining. Although the chance of benefit for phase 1 study participants is usually low, both parents and children frequently hold onto hope for a cure.

In this analysis, Victoria A. Miller, PhD, a CHOP psychologist and assistant professor of anesthesiology and critical care, and co-investigators audiotaped consent conferences for 61 patients ages 7 to 21 who were considering a phase 1 cancer trial. They transcribed and coded the tapes to examine what proportion of the conference was spent between each communication pair, for example physician-to-patient versus patient-to-physician.

The researchers also subcoded the communication by type: giving information, asking and checking, socioemotional, partnership, and social/personal. The majority of communication (73 percent) consisted of physicians “giving information,” which was not surprising, Dr. Miller said, because physicians often focus on full disclosure to meet informed consent regulations.

“When we’re looking at end-of-life decisions and communication with children and adolescents, though, giving all that information might come at the expense of other types of information that might be really important for kids at this time,” Dr. Miller said. “The socioemotional types of communication — things like rapport building, empathy, reassurance, and partnership building — might become lost.”

Another key finding, Dr. Miller said, was that even after controlling for age, patients who had physicians who communicated directly with them perceived that the information was easier to understand. Direct communication can show respect for children and adolescents as developing individuals and also may help them listen to and absorb the information.

“In general, I think it’s important for kids to be directly involved in their own healthcare, regardless of who makes the final decision,” Dr. Miller said. “Even if they don’t have full autonomy yet, there is a way to get their input. At a minimum, we should be asking kids: What do you think? Do you have concerns about what we’ve talked about today or about the different options?”

Particularly with older children and adolescents, the consenting physician should find some time alone with patients to answer any questions. This is potentially important because they might feel freer to share their concerns when their parents are not in the room.

“We know from other research,” Dr. Miller said, “that a frequent goal for parents at this time is to leave no stone unturned in their quest for a cure. And in that context, it might be difficult for kids to express their potential desire to stop disease-directed interventions or to express worries about their treatment choices. Meeting alone with providers could be one way to facilitate their comfort in talking about those things.”

This study, which was supported by the National Institutes of Health, can encourage physicians to use strategies that enhance meaningful patient engagement in all types of clinical trial enrollment, Dr. Miller said.

“It’s less about who makes the decision and more about the process of decision-making and how kids, parents, and providers interact with one another around decisions that need to be made,” Dr. Miller said.

How to best involve children in decisions about their health is a concept that permeates Dr. Miller’s work. She has an ongoing study that is examining children’s involvement in decisions about their enrollment in medical research at CHOP. Parents and children completed questionnaires assessing their perceptions of fairness, voice, and satisfaction with the decision-making process. Dr. Miller’s analysis of the data suggests that children’s involvement in research decisions has potential benefits.

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CHOP Researcher Advances Adolescent Care in Africa


A Children’s Hospital of Philadelphia pediatrician’s research project spans across continents to Botswana, a sub-Saharan African country with a busy clinic for 2,000 HIV-infected children and adolescents who stole her heart.

Elizabeth Lowenthal, MD, MSCE, remembers noticing a remarkable 12-year-old boy in Botswana, “a real leader” who spontaneously sat down and began translating for an American social worker who had recently arrived to organize a camp for patients. Smart and engaging, he did well on antiretroviral therapy until he became an older teenager. He struggled with his adherence, ended up failing his treatment, and became resistant to the medications.

Dr. Lowenthal brought this lesson to CHOP, along with many others that she learned while living for four years in Botswana, where she provided care as the clinical director of the Botswana-Baylor Children’s Clinical Centre of Excellence. She began practicing there in 2004, when the country was just getting antiretroviral treatment. Currently, more than 3 million children worldwide are affected by HIV, and more than 90 percent live in sub-Saharan Africa.

“Lots and lots of people in Botswana are infected, and just about everybody is affected one way or another by HIV,” Dr. Lowenthal said. “Botswana has better resources than most of the countries in sub-Saharan Africa, so figuring out what can work there hopefully can translate to where most of the kids are.”

As one of the only pediatricians at the time treating children with HIV in Botswana, Dr. Lowenthal became involved with government committees that were creating public health policies for the country. The committee members would turn to Dr. Lowenthal for recommendations for the pediatric population with HIV, but she found that there were little data in the literature to guide some of their decisions.

So while her heart was still in Botswana, she returned to the U.S. and began a research fellowship at CHOP to learn how to scientifically approach these questions. Dr. Lowenthal is now an assistant professor of pediatrics at CHOP, a staff physician at the Special Immunology Family Care Center, and lead research physician for CHOP Global Health.

In her first major research publication in the Journal of the American Medical Association, Dr. Lowenthal’s findings supported the use of efavirenz as initial antiretroviral treatment because it was associated with less virological failure when compared to another drug, nevirapine, which is used more commonly in children. The study influenced not only the treatment guidelines in resource-limited settings, such as Botswana, but it also helped to clarify U.S. guidelines.

Most of her current work is focused on adherence to HIV treatments among perinatally HIV-infected adolescents in Africa, a fast-growing population. Good treatment outcomes have allowed more children with HIV to reached young adulthood, and now they face unique challenges. As Dr. Lowenthal described in a recent Lancet Infectious Diseases review paper, they must confront psychosocial issues, negotiate decisions about sexual relationships, and manage a chronic illness during a period of rapid physical and psychological changes.

Unfortunately, this tumultuous time threatens the longevity of their treatment.

“While these treatments are lifesaving and amazing, they only work if you take them consistently,” Dr. Lowenthal said. “If they miss doses for a period of time, they develop resistance to them. Many adolescents, unfortunately, are losing the limited treatment options that they have. If we can’t support adherence well enough, all of these other problems are not going to be relevant because kids aren’t going to continue to survive.”

Her research projects take many perspectives to help predict which adolescents are going to have difficulty with adhering to their medication long-term. Recognizing those children who would most likely benefit from support services could be an important first step to possibly preventing their failure, Dr. Lowenthal said.

An ongoing study is comparing methods that measure adherence to determine which are the most useful among HIV-infected adolescents in Botswana. These methods include self-report, electronic monitoring devices, pill counts, medication refill rate, and monitoring virus suppression. Dr. Lowenthal’s research team also is considering how adolescents’ autonomy over medication is associated with these measurement methods.

In a pilot study published in AIDS Care, her research team evaluated the Pediatric Symptom Checklist (PSC) as a simple screening tool to identify children and adolescents with psychosocial needs. A prospective study is under way to assess whether high scores on the PSC precede adherence problems and treatment failure. Once these psychosocial areas are identified, healthcare providers could use them as starting points for interventions.

“In a setting where you have thousands of kids, trying to figure out what are the big issues that we need to approach is really important,” Dr. Lowenthal said. “They are certainly complex problems that need complex solutions. We are starting with just trying to understand what’s at the root.”

Dr. Lowenthal’s work in Botswana has crossover to her clinical work in the Special Immunology Family Care Center, where she and her team provide treatment for about 150 HIV-infected children. For example, artists at CHOP adapted a book created for children in Botswana to help initiate discussions about their HIV status. In the version for the American children, the good guys are superheroes instead of soldiers, and the kids play basketball instead of soccer, but the message is the same: Taking your antiretroviral medications keeps your body strong.

Dr. Lowenthal keeps in touch with some of her patients in Botswana, and her research allows her to visit two or three times a year. The amazing young man she met during her early years in Africa is now in his twenties and doing better again. Yet, she continues to ask: “What could I have done to have kept him from losing options and struggling during his teenage years?”

A CDC-PEPFAR Public Health Effectiveness Grant funds Dr. Lowenthal’s work, and additional questions related to optimizing adherence measurement and defining developmental and psychosocial factors associated with nonadherence are funded by an NIH K23 Career Development award.

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BWS Study Could Broaden Tumor Development Understanding


A new study by The Children’s Hospital of Philadelphia’s Jennifer Kalish, MD, PhD, into a rare disease could broaden researchers’ understanding of how numerous cancers develop. Dr. Kalish recently received an award from Alex’s Lemonade Stand Foundation to investigate tumor development associated with the rare childhood overgrowth disease Beckwith-Wiedemann Syndrome.

A genetic disorder that is often associated with overgrowth of the tongue (macroglossia), or a condition called hemihypertrophy in which one side of the body is larger than the other, Beckwith-Wiedemann Syndrome (BWS) occurs in approximately 1 out of 13,700 births. BWS is associated with an increased risk of childhood cancers, in particular the kidney cancer Wilms tumor and hepatoblastoma, a form of liver cancer.

Currently working in the laboratory of the University of Pennsylvania’s Marisa S. Bartolomei, PhD, Dr. Kalish is also an attending physician in the Division of Genetics. In late 2013 Dr. Kalish received a “Young Investigator” grant from the Alex’s Lemonade Stand Foundation to support her BWS investigation. A large portion of Dr. Kalish’s funding has also come from The University of Pennsylvania’s Institute for Translational Medicine and Therapeutics.

In addition to studying the clinical characterization of BWS, a major focus of Dr. Kalish’s research has been working to understand why some children with BWS develop tumors. “Up to 25 percent of children with BWS develop tumors, but we do not have a good understanding of why they do,” she said.

Because of their elevated risk of tumor development, all patients with BWS face rigorous, frequent cancer screening tests. Until they are four years old, patients must have blood drawn every six weeks, and must undergo abdominal ultrasounds every three months until they are eight years old. Though the screening is “pretty intense,” Dr. Kalish said the testing remains necessary because doctors cannot yet tell which BWS patients will develop tumors and which ones will not.

In an attempt to understand why only some children with BWS develop tumors, and to work to develop better screening markers, Dr. Kalish is currently conducting a two-part study. She is simultaneously developing a mouse model of the disease, as well as deriving induced pluripotent stem cells (iPSCs) from BWS patients’ fibroblasts. Mature cells that have been “reprogrammed,” iPSCs are capable of developing into many cell types. Dr. Kalish will use the iPSCs she creates to form liver cells to study how the BWS patient cells can develop into liver tumor cells.

The focus of the mouse model, meanwhile, will be on the role particular genes play in BWS and tumor development. Dr. Kalish’s investigations will focus on chromosome 11, as several genes’ expression there is altered in BWS and other cancers, including neuroblastoma, a form of childhood cancer that is responsible for 10 to 15 percent of all childhood cancer-related deaths.

“This region is dysregulated in other cancers, outside of BWS cancers, so there is clearly something about this region that is leading to tumors,” Dr. Kalish said. “BWS is an example of a rare disease that allows us to study a more common mechanism of disease, i.e. some types of cancer. We know that BWS patients have this genetic change because there is a phenotype. We do not know in adult patients with these other tumors if the tumors resulted from initial genetic changes on chromosome 11. It is just unclear at this time.”

“Because BWS patients’ tumor screening ends at age eight, clinicians and researchers do not necessarily know what happens to those patients in later years,” Dr. Kalish said. While the literature indicates that BWS patients have normal development, Dr. Kalish pointed out that the new investigation, coupled with the fact that she has been receiving BWS referrals from all over the country and the world, could give researchers the ability to take a more comprehensive look at BWS patients’ long-term health and tumor risk, both before and after age eight.

“Ultimately, we would like to have better markers to screen for, a better understanding of why these children get tumors, but most importantly possible treatments,” Dr. Kalish said.

To learn more about Beckwith-Wiedemann Syndrome, see the Hospital’s site. For more information about the numerous investigations currently underway at The Children’s Hospital of Philadelphia Research Institute, see the Research Institute’s page.

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Surgery Timing Affects Brain Injury in Infants With Heart Defects


Single ventricle heart defects, such as hypoplastic left heart syndrome (HLHS), are among the most complex and challenging forms of congenital heart defects to treat. They often require surgical repair in early infancy for survival.

Jennifer Lynch, a University of Pennsylvania physics graduate student who investigates biomedical optics at The Children’s Hospital of Philadelphia, researched how the timing of surgery influences brain injury in newborns with HLHS. She won Cardiology 2014’s Annual Outstanding Investigator Award for this study, and her contribution to the development of a novel tool to monitor brain metabolism and blood flow could help improve the care of these critically ill infants.

Infants with severe heart defects have a high prevalence of white matter injury, known as periventricular leukomalacia (PVL). White matter is the inner part of the brain that transmits information between the nerve cells and the spinal cord, as well as from one part of the brain to another. Babies with PVL are at higher risk for developing neurodevelopmental dysfunction, including cerebral palsy and intellectual or learning difficulties.

“These kids are very susceptible to brain injury because they’re not getting enough oxygen to their brain during this very fragile time when they’re just born and waiting to get their surgery and when they’re recovering from the surgery,” Lynch said. “The goal of the study was to see when they are most at risk for acquiring those injuries.”

Lynch works closely with Daniel Licht, MD, director of the Neurovascular Imaging Lab at CHOP and a member of the NeuroCardiac Care Program team. Their research focuses on how a portable noninvasive optical instrument — diffuse correlation spectroscopy (DCS) — developed at the University of Pennsylvania can provide information about blood flow to the brain.

They used this new technology in conjunction with near-infrared spectroscopy (NIRS), a noninvasive modality that provides information about tissue oxygenation. NIRS and DCS are diffuse optical techniques that make measurements by passing light through intact skin.

Currently, physicians rely on magnetic resonance imaging (MRI) to get a snapshot at specific time points to identify and quantify PVL. An advantage of using diffuse optical techniques is that they offer continuous monitoring at the bedside of cerebral blood flow and oxygen saturation, which allows physicians to get a more complete picture of how and when the injury occurs.

In this NIH-funded study, 37 infants with HLHS underwent pre- and postoperative MRI scans as well as continuous monitoring using NIRS/DCS. Lynch and her co-investigators noted that newborns who underwent surgery within four days of birth developed significantly less PLV.

The researchers also found some correlation between cerebral oxygen saturation measurements on the morning of surgery and the amount of white matter damage that the infants developed.

“We’re leading down this path where we think it’s this preoperative time period determining whether or not they acquire brain injury,” Lynch said. “Even though the brain injury doesn’t show up until a week later on the MRI scan, it seems to be predetermined preoperatively.”

In the future, Lynch said, diffuse optical monitoring of cerebral hemodynamic changes could help to predict which infants with HLHS are prone to brain injury and allow physicians to develop strategies to achieve optimal oxygen delivery to protect them from PVL.

Lynch received the outstanding investigator award at Cardiology 2014, the 17th annual update on pediatric and cardiovascular disease sponsored by CHOP. Held in Orlando in February, the conference gathered an international group of more than 1,000 medical experts. “It was exciting,” said Lynch, who attended the meeting for the first time and presented her abstract. “It was a great honor to win because a lot of amazing people were up for that award.”

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Early Childhood Bone Density Reference Data Needed


In the past decade, clinicians have made significant advancements in the diagnosis of pediatric bone disorders, particularly because national reference data is now available for bone density in children older than 5; however, clinicians do not have the appropriate tools for bone health assessment and research in early childhood.

A study at The Children’s Hospital of Philadelphia aims to address this gap by establishing reference data for children ages 1 to 5 using dual-energy X-ray absorptiometry (DXA), a test that measures bone density. The investigators also will examine factors that influence bone density and bone mineral accrual in this age group. Identifying children at risk for bone fragility is important because inadequate bone accretion may have lifelong consequences, such as susceptibility to fractures and osteoporosis.

“The first main goal of the study is to develop the equivalent of a growth chart for bone density,” said Babette Zemel, PhD, who is a co-principal investigator of the study. “Clinicians will be able to request a DXA scan, interpret it, and get an idea of where a child is relative to normal children of the same age, sex, and ancestry.”

Many serious clinical conditions in childhood threaten bone health due to inflammation and malabsorption, for example major cardiac disease, liver disease, and pulmonary disease. Or a child may have primary bone disorder that is genetic, such as osteogenesis imperfecta, which is characterized by bones that break easily, often from little or no apparent cause. Also, some young children with neuromuscular conditions have delayed gross motor skills and restricted mobility that may adversely affect bone accrual.

Accurate reference data will allow clinicians to identify bone deficits in these patient groups and to monitor how well treatment is working.

“It’s one thing for a healthy child to be running around, fall down, and break a bone, but there are some children who have pretty serious health problems, and they’re just not gaining bone the way that they should,” said Dr. Zemel, who is part of the division of gastroenterology, hepatology, and nutrition at CHOP and a research professor of pediatrics with the Perelman School of Medicine’s Institute for Translational Medicine and Therapeutics.

To give an idea of the scope of the problem posed by compromised bone strength, the Center for Bone Health team at CHOP looked at how many of the patients that they had treated who had already experienced a fracture, and it was more than 30 percent, Dr. Zemel said.

One of the challenges to conducting the current study is that toddlers cannot stay still long enough to complete a full body DXA scan. Dr. Zemel and her research team will use the latest generation of DXA technology, which provides more enhanced resolution that improves the accuracy for measuring small, less dense bones. They will conduct regional scans of the lumbar spine, forearm, and lateral distal femur that are feasible in young children because the scan time is 30 to 60 seconds, and the child can be held still without interfering with the scan.

Dr. Zemel anticipates that participant enrollment will open in April at two study sites — CHOP and Cincinnati’s Children’s Hospital Medical Center (CCHMC). Half of the study’s sample population will be African-American, and the other half will be non-African American. The study will involve a longitudinal cohort that will consist of 280 children ages 1 to 2 years who will be evaluated every six months for three years, resulting in data spanning ages 1 to 5 years. A cross-sectional cohort will include 240 children ages 1 to 1.5 years and 4.5 to 5 years who will undergo the same measurements at one time point. Data from both cohorts will be combined to create the reference curves.

Early childhood is a period of rapid development, so the researchers also will examine how changes in bone mineral content and density are related to growth, body composition, motor development, and physical activity. While previous research of older children has shown that greater growth status, more lean muscle mass, and more weight-bearing physical activity is related to higher bone density, Dr. Zemel pointed out that clinicians have little evidence that applies to the 1 to 5-year-old age range.

“With early identification of compromised bone health, improved awareness of the condition, and better understanding of the mechanisms involved, there is hope that this may soon translate into new and improved therapy for children at-risk for poor bone mineral accrual,” Dr. Zemel said.

An innovative part of the study is its application of new techniques for estimating body composition — the amount of muscle, fat, and bone in the body. A group of physicists from the University of California, San Francisco (UCSF) who are experts in bone and body composition imaging will use novel analysis to determine body composition from all of the children’s regional DXA scans, separating bone from soft tissue and air, and then calculating lean muscle and fat mass.

Since this technique is not yet validated, Dr. Zemel and her team will conduct anthropometric exams at all visits. Anthropometry is the collection of high quality body measurement data using standardized examination procedures and calibrated equipment. Trained anthropometrists will obtain skinfold thickness measurements that can be used in prediction equations, yielding excellent body composition estimates.

In a subset of 120 participants, the researchers will compare DXA and anthropometric body composition methods to the current gold standard, which uses isotope dilution to measure total body water and calculate fat and fat-free mass.

Heidi Kalkwarf, PhD, RD, a nutritional epidemiologist at CCHMC, is co-principal investigator of the study, which received funding from the National Institutes of Health.

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Electrocardiogram Use Varies for Infants With ALTEs


When frantic parents arrive at the emergency room and report that their infant experienced a frightening combination of symptoms including a prolonged lapse in breathing, change in color or muscle tone, or coughing or gagging, clinicians likely will describe the episode as an apparent life-threatening event (ALTE). Yet, it can be a frustrating conclusion because often these symptoms have resolved by the time the patient arrives at the ER, and the clinician is left to discern the exact cause.

The most common underlying diagnoses related to ALTEs are gastroesophageal reflux and upper respiratory illness. Clinicians also consider cardiac causes, but no standardized method is used to evaluate patients with ALTEs, especially with regard to electrocardiograms (ECGs) as a diagnostic tool. An ECG measures a heart’s electrical activity and generates a graphic representation, or tracing, that can indicate heart-related conditions.

A study team of physicians from The Children’s Hospital of Philadelphia’s Department of Pediatrics and Cardiac Center wanted to determine the prevalence of cardiac diagnoses in children who present with ALTEs and how often ECGs are used.

“This is the largest study of its kind and the first multicenter study looking into the evaluation of cardiac etiologies of ALTEs,” said Matthew D. Elias, MD, a CHOP pediatric cardiology fellow physician. “Hopefully it will contribute to the knowledge base of those providing for patients with ALTEs of what their institutions are using as a diagnostic workup for these patients and what other institutions are doing.”

Dr. Elias conducted the study with V. Ramesh Iyer, MD, MRCP, an attending electrophysiologist, and Meryl S. Cohen, MD, an attending cardiologist and director of the echocardiography laboratory. They reported their findings in the April issue of Pediatric Emergency Care.

The study team analyzed data from the Pediatric Health Information System database and found that ALTEs are relatively common, accounting for 2,179 hospital encounters at 43 children’s hospitals during a 15-month period from 2009 until 2010. Their analysis showed that 16 percent of these patients (355) had a cardiac diagnosis; however, due to the database’s limitations, the study team could not determine that cardiac pathology was related to the ALTEs.

The study’s main finding was that the hospitals had a wide range in the use of diagnostic ECGs, which highlights the absence of a systematic approach to ALTEs.

“Some hospitals almost never ordered an ECG, and others almost 100 percent of the time ordered an ECG,” Dr. Elias said. “On average, ECGs were ordered 43 percent of the time.”

When the study team looked deeper into the demographic information to determine any reasons why some patients with ALTEs would receive an ECG and some would not, the one statistically significant finding was that those patients who were older at presentation were more likely to have an ECG ordered.

“ALTEs typically present within the first three months of life, and if a patient were to present later on at several months of age, we think that those providing for the patients might expand their differential diagnosis and start suspecting a possibility of a cardiac disease,” Dr. Elias said.

This study raises a larger question for future research of whether or not ECGs could be helpful as a screening tool to detect or rule out particular cardiac diagnoses for patients with ALTEs.

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CHOP Honored Twice at Pennsylvania Bio Dinner


At the recent 2014 Pennsylvania Bio Annual Dinner & Awards Celebration, The Children’s Hospital of Philadelphia’s reputation as an international leader in pediatric medicine was further cemented, as the Hospital was honored with two awards celebrating its business and research innovations. CHOP was handed the “Deal of the Year” award for its successful spinout of gene company Spark Therapeutics, while the University of Pennsylvania and CHOP were jointly given the Patient Impact Award for their groundbreaking immune therapy research.

An organization devoted to ensuring Pennsylvania “is the global leader in the biosciences by creating a cohesive community,” with hundreds of members Pennsylvania Bio represents the “entire life sciences industry” in Pennsylvania. Each year the organization holds a dinner and awards ceremony to celebrate the previous year’s successes.

Based in part on the innovative work of Children’s Hospital’s Katherine A. High, MD, Spark Therapeutics, a “fully integrated gene therapy company,” was launched in October 2013 with a $50 million capital commitment from CHOP. According to the company’s website, Spark has “established human proof of concept in two organ systems — the eye and the liver — and are advancing a Phase 3 program in blindness caused by mutations of the RPE65 gene; a Phase 1/2 program in hemophilia B; and preclinical programs in neurodegenerative diseases and other hematologic disorders and forms of inherited blindness.”

The Pennsylvania Bio “Deal of the Year” award is intended for “a company that has promoted the growth of Pennsylvania’s bioscience industry by way of a substantial deal or strategic partnership,” closed in 2013. Other nominees for the 2013 award were Invisible Sentinel and small molecule-focused pharmaceutical company Tetralogic.

CHOP’s second award of the night, the “Patient Impact Award,” is for “a company or organization that has made a significant contribution to the quality of healthcare or length of life of patients in 2013,” according to the PA Bio web site. The Children’s Hospital of Philadelphia and the University of Pennsylvania were honored for their joint immune therapy research. In addition to CHOP/Penn, other nominees included medical device manufacturer Actuated Medical and Bethlehem, Pa.-based Orasure Technologies, which develops and manufactures diagnostic and oral fluid specimen collection devices.

Led at CHOP by Stephan A. Grupp, MD, PhD, and at Penn by Carl H. June, MD, the CHOP/Penn immune therapy partnership has been investigating using modified versions of patients’ own immune cells to attack — and destroy — tumors. Last year the partnership led to dramatic, extraordinary results: two children with acute lymphoblastic leukemia, the most common form of childhood leukemia, achieved a complete response after being treated with immune therapy. Since receiving the treatment one of those patients remains healthy and cancer-free.

“The Children’s Hospital of Philadelphia is thrilled to be honored with these two awards,” said Philip R. Johnson, MD, chief scientific officer of The Children’s Hospital of Philadelphia Research Institute. “They are a testament to the hard work of our investigators and staff, who work every day to improve the health of children.”

To learn more about the innovative research being performed at CHOP every day, see the CHOP Research site or the 2013 Annual Report.

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Injury Expert Dennis Durbin, MD, MSCE to Lead OCTR


Seasoned Children’s Hospital hand and injury researcher Dennis Durbin, MD, MSCE is set to succeed Mary Leonard, MD, MSCE as the director of CHOP Research’s Office of Clinical and Translational Research (OCTR). Currently co-Scientific Director of the Center for Injury Research Prevention (CIRP), Dr. Durbin will assume his new duties in June.

Since 2011, Dr. Leonard has directed the OCTR, which “assists clinical and translational investigators in identifying scientific opportunities and in forging productive collaborations” across CHOP and Penn. After nearly a quarter-century at CHOP and the University of Pennsylvania — having initially joined as a resident and fellow — Dr. Leonard is set to leave Children’s Hospital in June for Stanford University, where she will take on a number of roles: She will act as co-director of Spectrum Child Health, and will be the Founding Director of a new Center for Nutrition and Bone Health in Pediatrics and Medicine. In addition, she will serve as the Associate Division Chief for Research in Nephrology.

“Our loss is clearly Stanford’s gain,” said Philip R. Johnson, MD, the Research Institute’s chief scientific officer and executive vice president. “Mary will be missed not only by her colleagues in the Department of Pediatrics and the CHOP Research Institute, but also by her innumerable collaborators, mentees, friends, and the patients and families she has cared for over these many years.”

Taking the reins from Dr. Leonard will be CIRP’s Dennis Durbin, MD, MSCE. A Professor of Pediatrics at CHOP and Penn, Dr. Durbin is a member of the Division of Emergency Medicine and an Associate Scholar at the Center for Clinical Epidemiology and Biostatistics. An internationally renowned leader in pediatric injury prevention research, Dr. Durbin’s research has been particularly focused on the prevention of motor vehicle occupant injuries to children and the prevention of teen driver crashes.

He served as the co-principal investigator of Partners for Child Passenger Safety, a partnership between CHOP and State Farm Insurance Companies that resulted in the world’s largest child-focused motor vehicle crash surveillance system. Dr. Durbin has also served on various local and national committees including the Committee for Injury, Violence and Poison Prevention of the American Academy of Pediatrics, and has published papers in a number of journals.

Recently, Dr. Durbin was the first author of an editorial published in JAMA Pediatrics commenting on a recent JAMA Pediatrics study that examined the association between cortisol levels in teens and crashes and near crashes. On the CIRP blog, Dr. Durbin commended the cortisol-related research but cautioned that further work “is needed to better characterize the relationship between cortisol reactivity in response to stressors and crash risk in the general population of healthy teens and among those teens who might be at higher crash risk due to preexisting conditions, such as Attention Deficit/Hyperactivity Disorder.”

Until Dr. Leonard leaves CHOP in June, she and Dr. Durbin will work together to ensure a smooth transition. To learn more about the OCTR and its services, see the Office’s CHOP Research intranet page.

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Gene Therapist Beverly Davidson, PhD, Joins CHOP


Beverly L. Davidson, PhD, a nationally prominent expert in gene therapy, joined The Children’s Hospital of Philadelphia on April 1. She joins the Hospital’s Department of Pathology and Laboratory Medicine and will serve as the new director of the Center for Cellular and Molecular Therapeutics.

Prior to coming to CHOP, Dr. Davidson, who investigates gene therapy for neurodegenerative diseases, was associate director of the Center for Gene Therapy at the University of Iowa. She also served as director of the University of Iowa’s Gene Therapy Vector Core, and held the Roy J. Carver Biomedical Research Chair in Internal Medicine.

Dr. Davidson “will greatly enhance our abilities to translate important biological discoveries into pioneering treatments for deadly diseases,” said Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief. Dr. Davidson has been named to Children’s Hospital’s Arthur V. Meigs Chair in Pediatrics.

She has also assumed the role of director of the Center for Cellular and Molecular Therapeutics (CCMT), succeeding the Center’s inaugural director, Katherine A. High, MD. The CCMT is “dedicated to the understanding, development, and application of gene and related cell and nucleic acid therapies and the promotion of professional public education,” according to its website.

“I am thrilled that we have been able to recruit one of the premier translational investigators in the U.S. to serve as the next director of the Center. I have led the Center for the last ten years, and I eagerly look forward to the innovations of the next decade, under Dr. Davidson’s leadership,” said Dr. High.

In addition to her roles at CHOP Dr. Davidson is currently a member of the Scientific Advisory Board of the Hereditary Disease Foundation, and is Chair of Medical Sciences of the American Association of the Advancement of Science. She is also a scientific co-founder and advisor at the gene therapy company Spark Therapeutics, which launched in late 2013 with a $50 million capital commitment from CHOP.

Research Interests

Dr. Davidson’s research has been concentrated on inherited genetic diseases that attack the central nervous system, with a particular focus on childhood-onset neurodegenerative diseases such as Batten disease and similar disorders.  According to the NIH, Batten disease and related disorders affect “an estimated 2 to 4 of every 100,000 live births in the United States.”

In these disorders, the lack of an enzyme impairs lysosomes, proteins that perform crucial roles in removing unwanted by-products of cellular metabolism. Toxic waste products then accumulate in the brain and cause progressively severe brain damage. Dr. Davidson has developed novel methods to deliver therapeutic genes to the central nervous system. Her laboratory team has succeeded in reversing neurological deficits in small and large animal models of disease, and is working to advance this approach to treating human diseases.

In addition to lysosomal storage disorders, she has studied other inherited neurological diseases such as Huntington’s disease and spino-cerebellar ataxia. In these studies, she has delivered forms of RNA to the brains of animals to silence the activity of disease-causing genes. Some of Dr. Davidson’s recently published papers include a Neuron paper on microRNA binding sites in the brain, a Human Molecular Genetics study on functional microRNAs and target sites, and a paper published in Neurotherapeutics on RNA interference therapeutics.

Although much of Dr. Davidson’s work has centered on delivering beneficial genes to the central nervous system, the viral vectors that she has developed are applicable to other organs and tissues — for example, in gene therapy directed to the lungs or the liver.

For more information about Dr. Davidson and her research, see the Hospital’s press release about her appointment. To learn more about the pioneering gene therapy research being performed at Children’s Hospital, see the CCMT site.

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