Bench to Bedside

February 2016

Four Projects, One Goal: Curing Childhood Cancer


Curing childhood cancers is certainly no easy task, but researchers at The Children’s Hospital of Philadelphia are not deterred by a big challenge. Recent grants from CURE Childhood Cancer are supporting that work for four investigators at CHOP pursuing creative approaches to achieve this vision.

Developing Tiny Tumor Drug Deliverers

Many cancer treatments have harmful side effects when they act on healthy tissues in addition to cancer cells. A team led by Garrett M. Brodeur, MD, director of the Cancer Predisposition Program at CHOP, and funded by a CURE grant, is seeking ways to increase drug delivery to the tumors to improve drugs’ effectiveness while reducing their toxicity.

Their method uses tiny nanoparticles as delivery vehicles. Nanoparticles are a promising way to get drugs into tumors because tumor blood vessels are leaky, and the nanoparticles can enter the tumor much more easily than normal tissues.

“By increasing drug delivery to tumors by one or two orders of magnitude, we can achieve dramatically better anti-tumor effects while simultaneously decreasing total drug exposure to patients,” Dr. Brodeur said.

Dr. Brodeur’s team, including Co-Principal Investigator Michael Chorny, PhD, is developing and optimizing nanoparticles to carry and release two different targeted drugs into tumors. They will test the two nanoparticle-carried drugs in vitro in models of high-risk neuroblastoma, alone and in combination. The nanoparticles and drugs they are using could be used for other high-risk tumors, including sarcomas and brain tumors.

Understanding a Growth-Stopping Drug Candidate

A compound called JQ1 could potentially force cancer cells to lose their cancer identity and reprogram them as normal cells. That is one hypothesis that Margaret M. Chou, PhD, and her team will test in their study of the compound, which they have previously found to kill cancer cells in vitro and to curb tumor growth in animal models of the devastating bone cancer Ewing sarcoma. Their experiments are designed to find the mechanism of how JQ1 shuts down a pivotal protein involved in this disease.

“My laboratory is so grateful for CURE’s support of our work,” Dr. Chou said. “Ewing sarcoma is an incredibly difficult pediatric cancer to treat, and we hope that studies enabled by this funding will pave the way for the development of novel therapeutics.”

Finding Role of Mitochondria in Treatment Response

A team led by CHOP pediatric oncologist Richard Aplenc, MD, PhD, MSCE, received a second year of funding from CURE to continue its investigation of the role of mitochondrial DNA in the risks of relapse and infection in patients with acute myeloid leukemia (AML).

Mitochondria, the organelles inside cells that provide the body’s energy, have their own distinct genome, which Dr. Aplenc’s team will sequence from several hundred patients enrolled in a clinical trial for AML. Recent studies in adult cancers have indicated mitochondrial genes might play a role in different chemotherapy outcomes among patients, but researchers have not yet established such a connection in pediatric cancers.

Seeking Molecular Mechanisms of Resistance to Treatment

With a second year of CURE funding, CHOP pediatric oncologist Michael Hogarty, MD, is continuing another line of research on the role of mitochondria in pediatric cancer. Dr. Hogarty’s team is testing a hypothesis, supported by their preliminary data, that resistance to treatment in neuroblastoma tumors is caused in part by changes in the combined functioning of the cells’ mitochondria and another organelle, the endoplasmic reticulum (ER). If you think of the mitochondria as the powerhouse of the cell, then the ER would be the assembly line where proteins are built.

They believe that problems with the signaling mechanism between the ER and mitochondria could drive treatment resistance in cancer cells. They plan to validate whether alterations of this ER-mitochondria signaling are indeed predictive of cancer becoming resistant, and to understand the nature of the connections between alterations and resistance.

“With ongoing funding from this CURE award we are uncovering important clues into how cancer cells become resistant to available treatments,” Dr. Hogarty said. “This remains the single greatest barrier to improving cancer outcomes.”

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Early Smell Exposure May Be Critical for Sensory Development


Many parents try to offer their healthy babies a rich sensory environment, full of new sights, sounds, smells, and tastes, to stimulate the developing brain to appreciate life’s delicious complexities to the fullest. And for vision and hearing, there is a solid foundation of research showing that there is a critical period early in life when adequate stimulation of those senses is essential for their healthy development.

Now, a pilot study conducted at The Children’s Hospital of Philadelphia and published in the journal JAMA Otolaryngology provides some of the first-ever evidence for a critical period in developing the sense of smell, or olfaction, too. The findings have particular implications for rehabilitating young patients, including severely premature infants, who receive lifesaving medical interventions that temporarily prevent airflow through the nasal passages during this potentially critical period.

A group of such patients were the participants in the CHOP study. A third of the 18 participating children had undergone tracheostomy at or before age 4. At the time of testing they were still using that artificial airway, meaning that air did not flow past their nasal passages to expose them to scent stimuli as they breathed. Another third of the children had a past tracheostomy at or before age 4 for a period of at least six months, but at the time of testing they were breathing through their nasal passages. The remaining children were age-matched controls who were recruited from the otolaryngology clinic but never had a tracheostomy.

In smell tests, the children who had a current or past tracheostomy both performed poorly compared to controls — supporting the idea that the tracheostomy groups had missed a critical period for sensory development, and that later removal of the tracheostomy alone was not enough for a full recovery of olfaction.

“This was a little bit surprising,” said Will Kennedy, a medical student at the Perelman School of Medicine at the University of Pennsylvania, who was first author of the study. “There have been studies in the past in adults that show when you give adults a tracheostomy, they do recover the sense of smell and have robust smell abilities. If there was not a critical or sensitive period, kids should also regain a robust sense of smell.”

Without early stimulation of the neurologic pathways in the olfactory system, there seems to be a permanent and persistent deficit in smelling ability that persists later in life, noted Steven Sobol, MD, MSc, a CHOP pediatric otolaryngologist and surgeon and associate professor at Penn, and the study’s senior author.

“When dealing with critically ill children early in life, quality-of-life senses such as smell and taste are understandably not considered,” Dr. Sobol said. “One of the take home messages for us was that physicians should be aware there is this potential for smell dysfunction later on in life.”

Decreased sense of smell also has important safety implications, Dr. Sobol noted. Children and adults with limited olfaction may face dangers from consuming spoiled food and drink or from failing to detect the smells of smoke or gas.

For that reason, the team is next working on developing protocols for a type of smell rehabilitation that they plan to test in future studies. The process will involve exposure to malodorous compounds, such as those in gas and rotten food, that would be most essential to detect for safety. However, if their preliminary evidence suggesting that some children may have missed out on a critical period for olfactory development is correct, then rehabilitation may not work. Prevention strategies may be a better future approach.

“Being aware this is something that needs to be addressed, even though we don’t have the solution at this point, will eventually lead to therapies that will improve the eventual quality of life in these patients once they get through the early challenges,” Dr. Sobol said.

The study team noted that while their findings are intriguing, additional studies that follow children longitudinally would help confirm the existence of a critical period for olfactory development.

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Researchers Ask How Children With Autism Communicate Pain


When children with autism spectrum disorder (ASD) have acute medical needs, such as a broken bone or appendicitis, they are as likely to experience pain as any other child. But social and communication differences associated with ASD may cause clinical caregivers to miss cues showing that pain. This may compromise timely and accurate assessment and treatment. Recognizing this challenge, researchers at The Children’s Hospital of Philadelphia conducted a qualitative study that suggests clinicians should be prepared to ask children on the spectrum about pain in different ways.

The interdisciplinary study team set out to learn more about how these youth express and describe the experience of pain. They enrolled participants with an ASD diagnosis who came to CHOP for surgery and whose verbal language proficiency was sufficient to complete interviews about their pain during their hospital stay after their operation. The results were published in January in the Journal of Developmental and Behavioral Pediatrics.

While there are validated tools for measuring pain in nonverbal and cognitively impaired patients, those categories only sometimes overlap with ASD. The study participants’ individual preferences varied among different standard pain-measurement tools, such as a one-to-10 scale, or a similar common scale for children using a series of happy to sad faces. Many preferred to use words instead of numbers, and some preferred to show where it hurt, either by pointing on their bodies or drawing on a body-shaped outline on an iPad.

The study team determined that a variety of interactive methods and observations were necessary to assess pain accurately in these children, including asking about where it hurt, and about the characteristics and intensity of the pain, in ways that were meaningful to the child. Overall, they found that verbal children on the spectrum had a wide range of preferences for describing pain, and many relied on their parents as interpreters and advocates.

“We found the kids were quite able to describe their pain and used very sophisticated words sometimes, such as ‘excruciating,’” said Elizabeth Ely, PhD, RN, a nurse researcher and pain assessment expert at CHOP’s Center for Pediatric Nursing Research and Evidence-Based Practice, who led the study. “The words were descriptive, which helps you grasp what they’re feeling.”

Most of the young people with ASD had ideas about how to manage pain. Common methods included medication, distraction, and asking their parents for help.

Distraction is a common tool that many people use to deal with pain, whether on the spectrum or not, and at any age. But in this population, Dr. Ely noted, self-distraction may include engaging in repetitive behaviors or motions that are common among individuals with ASD — and that behavioral difference could stymie clinicians.

“Behavior is not the best way to understand pain in children with autism,” Dr. Ely noted, because the behavioral changes in these children are less likely to follow the typical, familiar patterns of other children in pain. “Think about the fact that the child has a source of pain and treat them accordingly. There is no evidence to say that children on the autism spectrum feel pain any differently, and they deserve adequate pain management. They can tell you what they think needs to happen, and their parents can tell you.”

Parents may be able to use their greater familiarity with their children’s behavioral responses to help interpret pain for clinicians if the child does not express it verbally. Several parents noted that they had gone through a learning process to recognize these cues in their child. Many of the children turned to their parents in their interviews for confirmation of their statements. As one participant stated, “Tell my mom. My mom understands my pain and what I need” — reflecting a common theme among many of the youth, acknowledging their parents’ ability to understand and help.

All of the interviews in the study were conducted by Dr. Ely and Kate Carpenter, MEd, CCLS, a child life specialist at CHOP. The research was funded by the Mayday Fund.

With study co-author Eron Friedlaender, MD, MPH, an emergency medicine physician at CHOP and professor at the Perelman School of Medicine at the University of Pennsylvania, Dr. Ely next hopes to build on this research with a quantitative study of potential differences in pain treatment for children with ASD. They are beginning to look at large datasets of electronic medical records to determine whether there are any systemic differences in the pain management children on the autism spectrum receive compared to typically developing children.

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New Research Affinity Group Supports Research Arena in mHealth


If you want to get in touch with a teenager, texting is the way to go. DYK (stands for “Did you know” in text slang), the Pew Research Center reported that 90 percent of teens with phones exchange texts, sending and receiving about 30 texts per day?

As part of their strategic visions, the medical and research communities at The Children’s Hospital of Philadelphia want to know how they can effectively capitalize on texting and other new avenues of communication with their young patients through mobile health (mHealth) initiatives. mHealth, also referred to as connected health, is the generation, aggregation, and dissemination of health information via mobile and wireless devices and the sharing of that information between patients and providers, according to the Healthcare Information and Management Systems Society.

“mHealth is a new paradigm of research in a lot of ways,” said Nadia Dowshen, MD, an adolescent medicine specialist at CHOP and an assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Dowshen is a co-chair of a new mHealth Research Affinity Group launched in January within the CHOP Research Institute. Two more co-chairs — Lisa Schwartz, PhD, behavioral science, and Linda Fleisher, PhD, MPH, health communications — bring a multidisciplinary perspective to the mHealth Research Affinity Group’s leadership team.

They are eager to bring together researchers and staff who are interested in exploring the ever-expanding array of technologies being used for mHealth, from basic text messages, apps and social media; to more complex wearable devices that link to electronic health records; to futuristic ideas such as implantable and ingestible devices. The new mHealth Research Affinity Group (mRAG) will provide a forum for researchers to meet and collaborate with other researchers who are interested in conducting mHealth projects.

“The mHealth Research Affinity Group will get the key players and stakeholders together to compare notes, experiences, and expertise to determine how we can best move mHealth research forward at CHOP,” Dr. Schwartz said.

About four years ago, Dr. Schwartz, a psychologist who works with children with cancer and their families at CHOP’s Cancer Center and an assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania, embarked on a Chair’s Initiative to test a mHealth texting intervention. Chair’s Initiatives are special projects supported by internal grants through CHOP’s Department of Pediatrics to tackle new models of care.

Dr. Schwartz aimed to see if texting could help adolescents and young adults coming off treatment for cancer to stay engaged in follow-up care and adjust back to life after cancer. Results from the randomized controlled trial showed that the intervention was feasible and patients’ responded favorably, but just as importantly, Dr. Schwartz discovered some of the challenging nuances of conducting mHealth research.

For example, she partnered with an outside vendor to build the platform and two-way text messaging features that her intervention required. Then she needed to see if business agreements were needed, sort out patient privacy issues, and figure out how to manage and analyze such a large amount of usage data. Dr. Dowshen encountered the same type of logistical concerns and learning curve when she designed a mHealth trial to improve adolescents’ adherence to antiretroviral medication using two-way text-messaging and an app with interactive features.

“All of those things take a tremendous amount of time and support,” Dr. Dowshen said. “A lot of us who were doing mHealth research were just slogging through on our own trying to figure out how to do this. When we all came together through the Chair’s Initiative mHealth Working Group, we were able to share how we did things. We thought it would be great to have a resource for everybody.”

Indeed, a survey conducted by the mHealth Working Group revealed that almost 50 percent of the 173 CHOP researchers who responded were interested in learning more about mHealth, and almost 35 percent were currently conducting mHealth research or quality improvement projects. Those already involved in mHealth research said they would welcome support in the areas of in-house development, information systems, and vetting commercial and academic partners.

At the same time, research funding opportunities for mHealth have begun to emerge, noted Dr. Fleisher, who is a senior scientist for the Center for Injury Research and Prevention at CHOP. Dr. Fleisher had developed numerous consumer mHealth tools and is currently leading a Chair’s Initiative with CHOP pediatrician Alex Fiks, MD, MSCE. This initiative, called Integrating Apps in Pediatric Practice (IAPP), is establishing and coordinating efforts to refine a process to develop and integrate consumer facing mHealth tools into practice.   They are focused on questions such as: “How do you begin to make those decisions about what technologies and what specific mHealth tools should get integrated into practice?”

An important aspect of mHealth, the three co-chairs pointed out, is that mobile technology is constantly changing. The mHealth Research Affinity Group members will help each other keep pace with this fast-moving field to ensure that their research activities remain relevant and are aligned with the latest mHealth trends.

Also, mHealth gives researchers opportunities to understand human health and behavior in more detailed ways, but the amount and type of data that it generates will require bioinformatics specialists who can relate their knowledge of mHealth data management and analysis.

For example, Dr. Dowshen’s study of two-way text messaging that took place over six months with 25 participants kept track of every text sent and received which generated thousands of data points. Other studies have used electronic signals from pill boxes or bottles to record adherence, but Dr. Dowshen found that her patients did not routinely use pill bottles or boxes to store their medication in order to protect their confidentiality. This type of data collection was feasible and acceptable for youth and allowed Dr. Dowshen to look at patterns of adolescents’ adherence to antiretroviral therapy in a way that previously would not have been possible.

While mHealth certainly has the potential to encourage patients to take more responsibility for their health and improve their quality of care, more evidence is needed to determine the best approaches for mHealth, from policy to implementation. Researchers will need to act quickly, as consumers’ expectations for mobile patient engagement continue to rise.

“Patients and families certainly want to use these new ways of communicating, but there is a lot of research to be done to understand how best to do that, who uses it, who doesn’t use it, and in what situations,” Dr. Fleisher said. “Although mHealth seems ubiquitous already, there is much we don’t know.”

For more information on the mHealth Research Affinity Group, contact,, or

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Researchers Test Magnetic Re-Seeding to Speed Blood Vessel Recovery


Reopening blocked blood vessels can mean the difference between life and death for many patients, including children with pulmonary hypertension and adults with coronary artery disease. But the procedure used for restoring blood flow can cause extensive vascular injury, wiping away an essential protective layer of cells lining the walls of arteries and veins: the endothelium.

It may take the body weeks or months to heal that damage. Some long stretches of damaged vessels may never fully regrow the endothelium, which naturally propagates inward from the healthy edge toward the center of the wiped-out area.

“Our idea is that if we could put some seeds of endothelium regrowth within the boundaries of this denuded arterial segment, so that the endothelium can grow from those foci, we could speed up the process dramatically,” said Michael Chorny, PhD, a researcher at The Children’s Hospital of Philadelphia and research assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, who specializes in developing delivery systems for therapies. “By changing the pattern of endothelium recovery, we may in practice restore it on scale of days.”

Speeding up this recovery process could prevent the clinical effects of endothelium loss by stopping them in their earliest stages. Endothelial cells perform many important functions. They protect the arterial walls from coming into direct contact with blood, maintain vascular homeostasis, and produce important molecules for blood vessel functioning.

When the endothelium is damaged, significant clinical problems can occur days, weeks, or even months later, including the rare problem of delayed formation of clots (late thrombosis) and the relatively more common re-hardening and re-narrowing of blood vessels (neoatherosclerosis) that is more aggressive than the original disease. These post-procedure effects are often worse in patients treated with a stent that releases antiproliferative drugs, because these drugs can interfere with endothelial regrowth.

To achieve the faster regrowth of endothelial cells and prevent these complications, the tricky part is getting the replacement endothelial cells into the right position in the damaged blood vessel. Dr. Chorny and a team of collaborators at CHOP are working on ways to pull them into place with the help of the magnetic force.

They have developed techniques to get cells, including endothelial cells, to take up biodegradable magnetic nanoparticles, and have shown that these nanoparticles do not impede cells’ biological functioning.

Magnetic nanoparticles have been in clinical use for years as an imaging agent. Simple methods also exist for deriving patient’s own endothelial cells in sufficient numbers, meaning that two steps underlying the approach are already clinically viable.

The researchers reported their latest progress in magnetically guiding these endothelial cells into damaged blood vessels in a living animal in the Journal of Controlled Release in January. The study was led by a team at CHOP including Dr. Chorny, cardiologists Ilia Fishbein, MD, PhD and Robert Levy, MD, and organic chemist Ivan Alferiev, PhD.

As part of this approach, the body is exposed to a strong, uniform magnetic field, which in future clinical applications could be generated by available equipment including magnetic resonance imaging (MRI) and magnetic navigation systems.

In the presence of this magnetic field, the nanoparticles inside cells become strongly responsive to the magnetic force. To focus this force in the diseased area, the researchers took advantage of magnetizable stents placed in the arteries — a structural support commonly implanted during the blood vessel reopening procedure that causes endothelial damage in the first place.

They showed that the magnetically guided endothelial cells were localized as intended in the region of stent placement, and that the number of cells increased over time in the week after delivery. In a comparison group where endothelial cells were not magnetically guided, the cells were not positioned effectively in the damaged stretch of the blood vessels. The next steps in research on this technique will be to work with larger animal models with human-sized blood vessels, Dr. Chorny said.

“We hope we can someday use this combination of magnetic field and a permanent or temporary stent to localize a patient’s own reintroduced endothelial cells, hopefully to achieve full restoration of the endothelium, not on the scale of months to maybe never, but in only hours or days,” Dr. Chorny said. “This way we may prevent the potential adverse effects associated with this fairly frequently used procedure.”

In other studies, Dr. Chorny has used magnetic guidance strategies to deliver different types of therapeutic agents, including small-molecule drugs, gene delivery vectors, and therapeutic enzymes. In the team’s ongoing studies focusing on restoring endothelium, they are also investigating combination techniques, such as using magnetic nanoparticles not only as a delivery method to position cells in the damaged parts of blood vessels, but also as a gene vector to make endothelial cells produce molecules that support regrowth — effectively re-seeding the scorched ground of blood vessels with cells that are their own fertilizer factories as well.

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Mitochondrial Expert Delves Into Ethics of Emerging Genetic Tools


Most of us learned in biology class that our nuclear DNA — 23 pairs of chromosomes shuffled from mom and dad — is responsible for assigning our genetic traits, from our eye color to our inherited disease risks. It is less commonly known that mitochondria, the energy factories in our cells, have their own genetic material (mitochondrial DNA, mtDNA) that is inherited only from mom. When mutations, or errors, occur in mtDNA that are transmitted from mother to child, they can pass on a diverse array of medical disorders associated with defects in energy production, energy balance, and other aspects of metabolism that often involve multiple organ systems.

Inherited mitochondrial diseases vary widely in presentation and severity, but frequently observed health consequences include metabolic strokes and seizures, muscle weakness and fatigue, problems with movement, heart problems, vision and hearing loss, and developmental delays. The most serious forms of mitochondrial disease can be debilitating, progressive, and even fatal at young ages. Estimates suggest that about 30,000 to 60,000 people in America have something wrong with the way their body generates energy, due to a primary mitochondrial problem originating at a genetic level in either the nuclear genes or mtDNA.

Couples who want to conceive a child, but who are at significant risk of their offspring manifesting serious mtDNA disease, may be interested in learning about sophisticated mitochondrial replacement techniques (MRT) that are under development but have not yet been conducted in humans in the U.S. These techniques involve modification of an egg (oocyte) or fertilized egg (zygote) by replacing the intended mother’s mitochondria that contains pathogenic mtDNA with mitochondria containing unaffected mtDNA from a female donor. The resulting child would have the nuclear DNA only of their intended mother and father, but due to the donor mtDNA contribution be genetically related to three individuals. Scientists do not expect MRTs will be 100 percent effective at depleting the abnormal mtDNA, but they anticipate only up to 1 or 2 percent of the original amount would remain, a level below that which is likely to cause disease.

While these novel techniques could one day offer families a new reproductive option, many medical and technical challenges and other safety and efficacy issues remain under question before clinical investigations of MRTs in patients could proceed under supervision of the Food and Drug Administration (FDA). Marni Falk, MD, an attending physician and director of the Mitochondrial-Genetic Disease Clinic at The Children’s Hospital of Philadelphia, participated in an expert committee convened by the Institute of Medicine (IOM), a division of the National Academies of Sciences, Engineering, and Medicine, at the request of the FDA to evaluate the ethical, social, and policy considerations of these techniques.

The IOM (recently renamed the National Academy of Medicine) is an independent, free-standing, objective body that evaluates the leading scientific dilemmas of the day to advance the nation’s health. Since it was established in 1970, some of the most seminal activities in medicine have been decided in IOM reports.

Over the past two years, Dr. Falk worked with the IOM committee, which included a diverse range of 12 experts from physicians, scientists, and ethicists to historians, lawyers, and patient advocates, to help them clarify the clinical and genetic implications of MRTs in the context of their ethical discussions. They came to a consensus and issued a report in February, “Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations,” that recommended that clinical research into MRTs should proceed with careful oversight.

“It was a great experience because of the unique opportunity to get to interact with such thoughtful people having deep expertise in policy and ethics and have them learn and carefully consider the broader implications of quite intricate aspects of science and medicine,” Dr. Falk said. “It was an intense process. To me, the most amazing part was that something about mitochondrial biology and disease had made it to this level of national interest and attention.”

The first mitochondrial DNA disease was recognized in 1988 by mitochondrial medicine pioneer Douglas Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine. It is a young field, and many people in clinical medicine are still learning about the subtleties and implications of mitochondria biology, genetics, and disease.

While mitochondrial dysfunction seems to be connected to many common diseases, Dr. Falk pointed out that the scope of her work on the IOM committee has the most implications for a specific subset of female patients who want to have their own genetic offspring and are at risk of transmitting a severe mitochondrial DNA-based genetic disease that could lead to a child’s early death or substantial impairment. For these prospective parents, the committee recommended that a “slow, cautious approach to MRT is justified” and that it is “ethically permissible to conduct clinical investigations of MRT subject to certain conditions and principles.”

Under this cautious approach, the committee recommended that MRTs initially should be studied only using male embryos, since males do not transmit mitochondrial DNA to their children. They also encouraged the FDA to pay special attention to communicating the novel aspects of this research to MRT research participants. For example, because MRTs require mixing mtDNA from a female donor with DNA from the nucleus of the mother and father, the researchers should investigate unanticipated health problems and possibly questions about identity, before regulatory approval or clinical use can occur for the techniques.

Three members of the committee, including Dr. Falk as the first author, wrote a Perspective article that appeared in the New England Journal of Medicine on MRTs’ implications for clinicians. The article begins, “Mitochondrial DNA (mtDNA) disease may be the poster child for highly targeted, ‘personalized’ medicine.”

“Even though MRTs would not confer health benefits on patients who already have mitochondrial DNA diseases, many patients with a known risk for transmitting such a disease to their offspring are highly motivated to prevent that from occurring,” Dr. Falk said. “That motivation is clear when we counsel patients and families affected by mtDNA disease, and recent patient surveys have reinforced that preventing disease transmission is a prevailing concern in this population.”

Dr. Falk also is an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

For more information, see the CHOP press release.

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New Brain Study Tailored for Nonverbal Children on the Autism Spectrum


The children who speak least — or not at all — are rarely represented in cutting-edge brain imaging research on autism spectrum disorder (ASD). Researchers at The Children’s Hospital of Philadelphia aim to change that with a new study enrolling children with ASD who are minimally verbal or nonverbal.

“This is really an underserved community who have not been given the opportunity to participate in research,” said Timothy Roberts, PhD, vice chair of research in the Department of Radiology at CHOP and a professor of Radiology at the Perelman School of Medicine at the University of Pennsylvania. “More importantly, the results of the research are not directly applicable to them, so even if we developed a drug for ASD impairments led by our biomarkers, we wouldn’t know if this treatment really was good for individuals with ASD with more limited verbal and cognitive ability.”

Dr. Roberts and colleagues from CHOP’s Center for Autism Research want to know whether certain aspects of neural rhythms and timing of neural firing that they found to be characteristic of ASD in previous studies, using noninvasive brain imaging called magnetoencephalography (MEG), are indeed common across the spectrum.

“When neural activity is happening, it produces electrical and magnetic fields,” said J. Christopher Edgar, PhD, a co-leader of the study and a clinical neuropsychologist and brain imaging researcher in the Department of Radiology at CHOP. “We use this machine to measure the magnetic field. We do that to look at brain function.”

The neural biomarkers that Dr. Edgar and Dr. Roberts have found correlate with the level of clinical impairment in the children they have studied to date, particularly in the realm of language ability.

“There is a scientific question: Does this correlation extend into this nonverbal and minimally verbal population in a continuous way, or is it a separate disorder?” Dr. Roberts said. “I suppose a fundamental question is: Is the autism spectrum continuous or discrete in terms of these brain markers?”

To better define how specific these brain markers are for ASD, or to identify possible neural brain measures shared across neurodevelopmental disorders, the study will also include children with intellectual disability without ASD.

Innovative Study Creates Unique Behavioral Plan for Each Child

A significant innovation in the CHOP team’s new study is how they designed it for inclusion of minimally verbal and nonverbal children. The team calls the approach MEG-PLAN (MEG Protocol for Low-Language/Cognitive Ability Neuroimaging). It tailors the study participation experience to each child by engaging with parents as partners early and throughout the process. Study Co-leader Emily Kuschner, PhD, spearheads this behavioral aspect of the study design and its emphasis on taking the standard effort at autism-friendliness in research to a new, more personalized level.

In MEG-PLAN, Dr. Kuschner and the study team will work with parents to conduct a “mini” functional behavior assessment to identify difficulties or behaviors that might arise when children come in for the MEG visit. The research team will become familiar with the child’s particular sources of motivation and anxiety before the child visits the hospital. This helps the researchers to customize each child’s experience to minimize negative stimuli and to offer personally meaningful forms of positive reinforcement, such as favorite songs, toys, or foods, to reward participation. In essence, they create a unique behavior plan for each child participating in the study.

Parents and caregivers will receive videos and CDs to help prepare their child for participation. The video will help them know what to expect, and audio recordings will familiarize (and desensitize) them to the sounds of the MEG machine.

The research team will also rely on parents and caregivers to facilitate effective communication with their nonverbal and minimally verbal children. For example, parents are likely to know their child’s nonverbal cues well enough to recognize whether he or she has understood a request, or to recognize when they need to take a break. Parents and caregivers will work hand in hand with the study team throughout the visit; the process will be extremely collaborative.

Study Technology Tailored to Population’s Unique Needs

The CHOP team also designed technical aspects of the study to ensure success by measuring neural processes that happen automatically when the brain is stimulated, such as auditory nerve signaling when the child hears a sound. This way, the children do not need to consciously follow any instructions or complete any tasks for the scan in order for the researchers to receive useful information about their brain signaling patterns.

Under MEG-PLAN, participating children are also not required to hold extremely still while undergoing brain scans — a requirement in other studies that often makes minimally verbal and nonverbal children ineligible. Magnetic Resonance Imaging (MRI), which requires children to remain motionless for an extended period, was eliminated from the MEG-PLAN study protocol. The researchers will use age-matched template MRIs instead of the individual participants’ own MRIs to enable mathematical interpretations of MEG scans. In addition, they have developed motion-tracking methods and algorithms to compensate for minor or moderate movements a child may make during MEG scanning, which is sensitive to motion but less so than MRI.

Dr. Roberts noted that, if successful, the behavioral aspects of their study design could translate well to other studies, and even other study populations who are less able to participate, hold still, or follow instructions during brain scans, such as younger children and infants. The technical aspects of MEG-PLAN are fairly specific to conducting MEG studies, which are only conducted at a few centers including CHOP — but could still prove useful for future MEG research as well.

A Signature Project of CHOP and Penn Research Strengths

Research using MEG to detect novel brain measures (biomarkers) with which to diagnose and evaluate minimally verbal individuals on the autism spectrum is the signature research project of the Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP and Penn. This IDDRC center recently received renewed funding for the next five years from the Eunice Kennedy Shriver National Institute of Child Health and Development, its sixth successful and consecutive IDDRC grant application since its establishment in 1990. It is one of 15 centers in the national IDDRC network, which represent the nation’s first and foremost sustained effort to prevent and treat disabilities through biomedical and behavioral research.

On CHOP and Penn campuses, the IDDRC promotes intellectual and developmental disability related research through advocacy, education, and research support for investigators. It offers core laboratory services in areas including analytical neurochemistry, biostatistics and bioinformatics, clinical translational research, neuroimaging and neurocircuitry, and preclinical models. For more information about the IDDRC, contact Kristen Hearty at

The MEG-PLAN study is recruiting participants now, including school-age children (age 8 to 12 years) with ASD who are minimally verbal or nonverbal, and children with cognitive disabilities but not ASD (including those with 22q deletion syndrome, spina bifida, trisomy 21, Turner Syndrome, and intellectual disability with no known etiology). For more information, contact 267-426-6373 or

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Statewide Action Plan to Curb Overprescribing of Psychotropic Medications


Research conducted by PolicyLab at The Children’s Hospital of Philadelphia laid the groundwork for new statewide initiatives that aim to reduce the use of psychotropic medications among Pennsylvania children in the foster care system who are enrolled in Medicaid.

At a press conference Tuesday, Feb. 23, announcing the changes, David Rubin, MD, MSCE, director of PolicyLab and a CHOP pediatrician, recalled the case of a bright 5-year-old boy who had experienced abuse and neglect before entering the state’s foster care system. Several day care directors had dismissed him from their programs due to his disruptive behavior. By the time the boy’s foster mother introduced him to Dr. Rubin, the child already had been prescribed two different psychiatric medications, and his physician had recommended adding an antipsychotic medication with sedative qualities.

Psychotropic medications are a class of drugs that is used to treat or manage mental health symptoms or challenging behaviors. Antipsychotic medications, which are primarily used to manage psychosis in serious mental illnesses such as schizophrenia and bipolar disorder, fall under this category. Since they can have significant side effects, antipsychotics should be prescribed under careful consideration and subject to ongoing monitoring over time.

“These medications increasingly are being prescribed off-label to control behaviors of kids who are acting out,” Dr. Rubin said. “There are approved indications for those types of medications, but principally we’ve seen the growth over time in the use of medications like antipsychotics to control disruptive behaviors by in essence sedation.”

He worried about the potential risks and long-term consequences of these medications on the precocious 5-year-old. Ideally, a trauma-based care model and alternative nonpharmacological psychosocial interventions perhaps could have made a difference, he said. Yet those types of services often are difficult to access or coordinate and seem too complicated for families in crisis who are looking for a “magic bullet” solution.

Unfortunately, the boy’s story is all too common. PolicyLab research commissioned by the Pennsylvania Department of Human Services has shown that the use of psychotropic medications was three times higher among 6 to 18-year-olds in foster care than among youth in Medicaid overall. More than half of youth antipsychotic users in Medicaid had a diagnosis of attention-deficit/hyperactivity disorder. The majority of these youth did not have another diagnosis that clinically indicated the use of antipsychotics.

In response to PolicyLab’s research and analysis, DHS partnered with experts from CHOP, the American Academy of Pediatrics, and the Pennsylvania Psychiatric Society last year to start taking a serious look at psychotropic prescribing practices for children.

“This has truly been a team effort and a testament to what can happen when government throws open the doors and doesn’t huddle in a corner and try to do things by themselves but reaches out to the experts in the field to give us their guidance and input to hopefully turn around this issue,” said DHS Secretary Ted Dallas. He announced several steps his office will take to address this critical issue:

“We think all of these things in combination will have a huge impact on the prescription of psychotropic drugs for children in Pennsylvania, and hopefully it may also be something that folks in other states may want to take a look at,” Dallas said. “While we’re very happy with the progress we’ve made, we are by no means satisfied. We know there is a lot more to do. Working with our partners at CHOP and PolicyLab, I have no doubt that we’re going to continue to make progress.”

Kathleen Noonan, JD, PolicyLab co-founder and CHOP’s Associate Vice President of Board Relations, served as the co-chair of the psychotropic subcommittee of the DHS Committee on Foster Care and Health. In that role, she helped create recommendations for how the commonwealth could address this problem.

“At PolicyLab, we believe that producing academic literature is not sufficient. In order to have an impact, you have to do things,” Noonan said. “An evidence to action mission means you have to get on the train and go to Harrisburg and D.C., and that’s what we do.”

For more information, see the DHS press release and PolicyLab’s website for more background on the issue of psychotropic prescriptions among children in foster care and enrolled in Medicaid.

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

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