Sep 04 2014

Award Set to Fund Opioid Withdrawal Investigation

opioidEvery year, approximately 350,000-400,000 infants are treated in a neonatal intensive care unit (NICU), according to a report put out by the Health Resources and Service Administration. Of those, between 50 and 80 percent become dependent on the opiates—such as the powerful analgesic morphine—they are prescribed for their pain. And per the Drug Enforcement Agency, morphine “has a high potential for abuse,” but is also “one of the most effective drugs known for the relief of severe pain and remains the standard against which new analgesics are measured.” This means that clinicians trying to manage their patients’ pain know the same treatments that ease their pain could lead to dependence and withdrawal later.

Currently, the “mainstay of pharmacologic management is gradual opioid weaning,” note the authors of a 2010 Pediatrics paper on opioids in children. Specifically, neonates are often weaned with methadone, pointed out The Children’s Hospital of Philadelphia’s Gordon A. Barr, PhD.

“There’s no good treatment,” for opioid dependence in infants, Dr. Barr said. “People have tried benzodiazepine, they’ve tried barbiturates, they’ve tried keeping the lights really low and dim and quiet—those environmental conditions help calm the baby, but they don’t slow the withdrawal process.” But the standard of care remains lowering the methadone dose gradually, he said.

Director of the Section of Acute and Chronic Pain Management in Children’s Hospital’s Department of Anesthesiology and Critical Care Medicine, Dr. Barr recently received a grant from the National Institute on Drug Abuse to examine the immune system’s role in opioid dependence during early development. Over the course of this two-year, exploratory R21 award, Dr. Barr plans to look “at whether modulation of immune function has the same consequences for opiate actions in infancy as it does in adults,” he said. “And if so, how?”

This project grows out recent “attention paid to he interactions of the immune system and brain function in general, and opiates and immune function and brain function in particular,” Dr. Barr noted. In addition to relieving pain, opiates are known to act as immunosuppressors, but how they do so in neonates remains poorly understood and understudied. There is a paucity of literature on opiate action during early development, Dr. Barr pointed out.

Preliminary research by Dr. Barr’s laboratory shows that activating the immune system during treatment actually worsens opioid withdrawal, and that doing so in very young neonates (mice younger than seven days old, or full-term human babies) has no effect. With this investigation, Dr. Barr will be specifically be looking at the immune receptor toll-like-receptor 4 (TLR4). Dr. Barr and his team’s hypothesis is that TLR4 in the nervous system is not functional in very young neonates, hence the lack of reaction observed when the immune system is activated during opioid treatment.

The investigators plan on evaluating a number of drugs, including some already approved for other uses and experimental drugs not yet on the market. Though pre-clinical, basic work, Dr. Barr’s hope with this project is that it will help inform clinical decisions in the future, and help to determine whether need exists for new drugs to be developed.

To read more about this study, see the August issue of CHOP Research’s Bench to Bedside . And to learn more about pain management, see the Department of Anesthesiology and Critical Care Medicine’s Pain Management Program.

Permanent link to this article: http://www.research.chop.edu/blog/award-set-fund-opioid-withdrawal-investigation/

Sep 02 2014

Study Compares Lung Opening Strategies for Preterm Infants

infantWhen an infant is born, we usually think of the strenuous effort labor entails for the mother, but it also requires a fair amount of work on the baby’s part.

A newborn quickly has to adapt to breathing air, which calls for a large set of events to take place. In the fluid-filled environment of the uterus, the lung is essentially closed, and the infant has to expand the lung quickly, in order to take over the placenta’s business of putting oxygen into the bloodstream and getting rid of carbon dioxide.

That becomes a tricky thing to do for a baby who is born prematurely and extremely small — less than 1,000 grams — because the infant must have good muscle power to generate the high opening pressure required for its first breath to establish lung volume. This is where a research maneuver being studied by a multicenter, international clinical trial led by Haresh Kirpalani, BM, MSc, of The Children’s Hospital of Philadelphia, and Sarah J. Ratcliffe, PhD, of the University of Pennsylvania Perelman School of Medicine fits in.

Previously, several large trials have looked at helping infants who weigh less than 1,000 grams to expand their lungs using a simple, low level continuous positive airway pressure, called CPAP, which is administered in the delivery room via a facemask at about 5 to 7 cmH2O. And while it’s been shown that CPAP can help the baby transition into a postnatal, oxygen-enriched environment satisfactorily, many of these babies end up requiring placement of an endotracheal tube in the windpipe that breathes for the baby. Intubation imposes an additional burden and risk of bronchopulmonary dysplasia, one of the main problems that face premature babies if they survive.

The research maneuver being tested in the Sustained Aeration of Infant Lungs Trial (SAIL) launched this summer will impose a higher peak inspiratory pressure of about 20 cmH20 and hold the breath for about 15 seconds immediately after birth to facilitate uniform lung aeration. Half the babies enrolled in the trial will receive the low level CPAP, and the other half will receive the research intervention delivered by a physician trained to implement the study protocol. A potential concern is that the higher pressure will increase the chance of air leaks, but so far the literature is not convincing that this is a problem, Dr. Kirpalani said.

“The results of the trial should enable us to take a near definitive look at the standard of care for resuscitation of these babies at delivery, and begin to give some guidance to the Neonatal Resuscitation Program as to whether sustained inflation is a useful strategy or not,” Dr. Kirpalani said.

The NRP is an educational program sponsored by the American Academy of Pediatrics and the American Heart Association to teach an evidence-based approach to resuscitation to multidisciplinary hospital staff who care for newborns at the time of delivery.

The SAIL research team expects over three years to enroll 600 infants with a gestational age of at least 23 weeks but less than 27 weeks who require resuscitation or respiratory intervention at birth. A particular challenge of this study is approaching parents during the stressful and uncertain time of preterm labor and gaining full parental consent to participate in the trial.

In a Pediatric Perspectives article published in the July issue of Pediatrics, Dr. Kirpalani and his neonatology colleagues at CHOP, Sara B. DeMauro, MD, and Barbara Schmidt, MD, MSc, and also at McMaster University, Canada, Janice Cairnie, RN, and Judy D’Ilario, RN, examined the importance of honesty, trust, and respect during consent discussions in neonatal clinical trials.

“We’ve always been of the mind that an ongoing dialogue after consent is extremely important to enable the parents to understand what the issues are and also to reinforce throughout the trial duration that we are conducting it largely because we do not know whether treatment A or treatment B is better,” Dr. Kirpalani said. “That gives parents multiple opportunities to revisit the informed consent question, allows them to voice their concerns, and understand their child’s potential benefits and risks. In a way, it should be like an ongoing part of the therapeutic relationship.”

The SAIL trial is supported by funding through the Eunice Kennedy Shriver National Institute of Child Health and Development.

Permanent link to this article: http://www.research.chop.edu/blog/study-compares-lung-opening-strategies-preterm-infants/

Aug 28 2014

Report on 100 Prenatal Surgeries for Spina Bifida Support it as New Standard of Care

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

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

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

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

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

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

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

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

For more details on the study, click here.

Permanent link to this article: http://www.research.chop.edu/blog/report-100-prenatal-surgeries-spina-bifida-support-new-standard-care/

Aug 26 2014

Investigators Excited to Receive CPCE Pilot Grant Awards

CPCE

The spring 2014 award winners are Andrea Knight, MD, and Lori Kestenbaum, MD.

Medical research is a rewarding field to work in, but young investigators often find that while they have an abundance of bright ideas, scientific funding is not as plentiful. Any opportunity to get a research project off the ground is greatly appreciated, especially by the two Children’s Hospital of Philadelphia physicians who recently received 2014 Pilot Grant Awards from the Center for Pediatric Clinical Effectiveness (CPCE).

The purpose of the CPCE’s Pilot Grant Program is to promote and support fellows, junior faculty, and other CHOP researchers in conducting clinical effectiveness pilot research studies that will attract external support for large-scale studies. The CPCE accepts proposals twice a year, and promising projects undergo at least two rounds of reviews to determine that they fully meet the selection criteria. Candidates must be involved in research designed to produce evidence for what works best for treating, diagnosing, and preventing disease.

The spring 2014 award winners, Andrea Knight, MD, and Lori Kestenbaum, MD, are enthusiastic about launching their investigations.

Dr. Knight is an assistant professor in the Division of Pediatric Rheumatology at CHOP. Her research focus includes patient-centered outcomes and health services research in pediatric systemic lupus erythematosus (SLE), also known as lupus, an autoimmune disease that can affect multiple body systems. Her goal is to facilitate access to mental healthcare and improve health-related quality of life for children with SLE.

The pilot study aims to reveal key patient, caregiver, and provider-level factors that affect mental healthcare for pediatric SLE and mixed connective tissue disease patients (MCTD). The findings from this study will lay the groundwork for developing mental health screening and intervention options for pediatric patients with SLE/MCTD. Practitioners could use this knowledge to create a trusting environment that allows patients with chronic diseases to feel secure in expressing their mental health concerns and to more easily obtain appropriate mental healthcare.

“Ensuring that their mental health is adequately addressed is important because they have a lot of psychological stress dealing with their chronic conditions,” Dr. Knight said. “We want to gain some rich information from patients and their families about their mental health needs and any difficulties that they see to getting them addressed.”

The pilot grant will build on previous findings that Dr. Knight compiled as the principal investigator for a study evaluating the prevalence of depression and anxiety in pediatric SLE patients. She found that depression or anxiety affected about one-third of the patient cohort, but that mental health treatment rates in those with symptoms were low.

Over the next year, Dr. Knight and her study team will conduct patient-centered interviews with 30 participants that will aim to identify possible barriers to the mental health referral process. This experience also will allow Dr. Knight to expand her expertise to include more qualitative research processes.

“Surely, having funding toward a project is hard to capture these days, so it was very exciting to win the grant,” Dr. Knight said. “It also is exciting to know that the CPCE, policy lab, and CHOP as a whole are interested in this issue. I personally think that it is very important to my patients but also to chronic disease patients as a whole.”

The second recipient of the award, Dr. Kestenbaum, is a fellow in Pediatric Infectious Diseases at CHOP. Her research is focused in two areas: understanding vaccine hesitancy to increase vaccine acceptance and modifying antibiotic prescribing practices for common childhood illnesses to reduce antibiotic overuse.

The pilot study will investigate antibiotic prescription practices and efficacy in patients with community-acquired pneumonia (CAP). CAP is the leading cause of mortality for children beyond the neonatal period worldwide, and current guidelines recommend amoxicillin as first line treatment to target the most common causes of CAP. Despite these guidelines, the most commonly prescribed antibiotics are macrolides, a class of antibiotics that does not appropriately treat the most common causes of bacterial pneumonia.

“The [study] design takes advantage of CHOP’s practice-based research network, which is an invaluable resource in the fact that it links together 31 primary care practices, multiple different regions, socioeconomic classes, and is all united under one electronic health record,” Dr. Kestenbaum noted.

The study will entail a thorough analysis of a dataset from the ambulatory EHR system in order to pinpoint patient and provider characteristics that are likely to influence antibiotic prescribing choices in the outpatient setting. Afterward, Dr. Kestenbaum will manually review additional data to compare how treatment regimens with amoxicillin vs. macrolides are associated with patients’ outcomes.

“This study will look at what drives providers to make treatment decisions,” Dr. Kestenbaum said. “Is it something about the patient, is it something about the provider, or is there another factor that drives providers to make treatment decisions that are not in our national guidelines?”

Dr. Kestenbaum expects that results of this comparative effectiveness pilot study will help to support future guideline development and implementation to ensure appropriate antibiotic prescribing practices for the management of CAP.

“The opportunity to have a pilot grant is really exciting,” Dr. Kestenbaum said. “It allows me to collect preliminary data to support future study proposals. The support of the CPCE for those of us who are just starting out is incredibly helpful.”

Permanent link to this article: http://www.research.chop.edu/blog/investigators-excited-receive-cpce-pilot-grant-awards/

Aug 22 2014

Award Will Support Novel Hemophilia Therapy Investigation

hemophilia

Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX).

The Children’s Hospital of Philadelphia’s Lacramioara Ivanciu, PhD, was one of five investigators who recently received funding through the Bayer Hemophilia Awards Program (BHAP). A “unique initiative dedicated to supporting innovative research and educational initiatives that benefit people with hemophilia,” the BHAP is administered by Bayer Healthcare, a subsidiary of the German pharmaceutical giant Bayer AG, and awards grants to hemophilia investigators and professionals.

An investigator in the Children’s Hospital’s Division of Hematology, Dr. Ivanciu’s research is focused on the design of novel bypass agents for the treatment of hemophilia. An inherited bleeding disorder, hemophilia is a lifelong disease that can require chronic management According to the CDC, each year in the U.S. approximately 400 babies with hemophilia are born.

Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX). A key part of the coagulation system, FIX deficiency results in Hemophilia B, which is most often treated by replacement FIX therapy. However, FIX replacement therapy requires multiple injections and high doses, as FIX has a short half-life.

“My research focus on bioengineering coagulation factor IX as a potential alternative strategy for hemophilia B therapy,” said Dr. Ivanciu. “The novel FIX variants are expected to have prolonged half-life and efficacy and thus, be more efficient at lower doses. This could greatly benefit the patients with hemophilia by reducing the therapeutic dose, an important goal in the replacement therapy,” said Dr. Ivanciu.

In addition, Dr. Ivanciu recently co-authored a paper published in Blood examining recombinant activated human Factor VII, and was the first author another paper also published in Blood that focused on two other coagulation factors, factor Xa and factor Va.

Saying she was “very pleased” to receive the BHAP Early Careeer Investigator award, Dr. Ivanciu noted that its support will allow her “to advance the understanding of bleeding disorders by developing and applying new systems models and therapeutics to these problems.”

“I am in a unique position to make meaningful contribution to the field and possibly advance new therapies for the treatment of hemophilia,” she added.

“BHAP, now in its twelfth year, continues to attract high-quality applicants who are committed to answering important scientific and medical questions. Through our support of their research, this year’s winners will contribute to a better understanding of hemophilia and bleeding disorders and ways to improve treatment and optimize patient outcomes,” said Bayer Healthcare’s Prasad Mathew, MD.

For more information hematology research and care at The Children’s Hospital of Philadelphia, see the Division of Hematology’s website.

Permanent link to this article: http://www.research.chop.edu/blog/award-will-support-novel-hemophilia-therapy-investigation/

Aug 20 2014

New Study Focuses on Nasal Steroids as OSA Treatment

nasal_steroidsRemoving a child’s tonsils and adenoids, or adenotonsillectomy, currently is the primary therapy for childhood obstructive sleep apnea syndrome (OSAS), but many parents remain wary about surgery and would welcome an alternative approach. Researchers from the Sleep Center at The Children’s Hospital of Philadelphia are set to launch the “Steroids for Pediatric Research in Kids (SPARK)” trial in September that will investigate the use of nasal corticosteroids as a possible treatment for OSAS.

OSAS is extremely common, according to Carole L. Marcus, MBBCh, director of CHOP’s Sleep Center. It is seen in 2 to 4 percent of children, but she maintains that it is greatly underdiagnosed. Usually, a blockage from enlarged tonsils or adenoids cause obstruction in breathing, called apneas and hypopneas, that repeatedly disrupt a child’s sleep. If OSAS is left untreated, it can result in significant complications, ranging from behavioral problems and sleepiness in mild-to-moderate cases, and cognitive abnormalities, high blood pressure, and growth disturbances in more severe cases.

One of the lessons that Dr. Marcus learned from being a co-investigator of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT Study) — a large, randomized, multicenter control study that compared the effectiveness of surgery vs. watchful waiting for OSAS — was that better treatments and more therapeutic choices for families are needed. While adenotonsillectomy is relatively safe, about 3 percent of children will have significant hemorrhage postoperatively, and other complications can occur.

“Most families were hoping to hold off on surgery because they were scared,” Dr. Marcus said.

Over the past few years, several small, short-term studies have reported on nasal steroids as an alternative treatment for pediatric OSAS. They showed overall benefit for mild OSAS cases but did not study more severe cases; in addition, the results demonstrated tremendous individual variability. The American Academy of Pediatrics clinical practice guidelines for the diagnosis and management of OSAS issued in 2012, which Dr. Marcus chaired, included nasal steroids as a treatment option, but there was not enough evidence to give a strong recommendation.

Dr. Marcus and colleagues are launching the SPARK study to increase knowledge about the effect of nasal steroids and to identify which subgroups of patients with OSAS are most likely to benefit. For example, the research team will determine if children with asthma and/or atopy respond better to nasal steroids. Another subgroup they will focus on is African-American children because strong data from CHAT and other studies have shown that they have more severe OSAS and do not respond as well to surgery. Sophisticated genetic tests included in the SPARK study will help the investigators to further characterize responders vs. non-responders.

The double-blind, randomized control trial also will assess nasal steroids’ duration of action and possible side effects, which for a small minority of children include growth problems, ocular abnormalities, and adrenal suppression.

“Does the disease recur if you stop nasal steroids?” Dr. Marcus asked. “Is it cured forever? Do you keep doing sleep studies? If kids are on the steroids long-term, are you likely to see complications?”

In order to answer those questions, the study is designed to randomize children to receive either nasal steroids or placebo for three months. After three months, those in the nasal steroid arm of the study will be re-randomized to either ongoing steroids or placebo for another nine months.

The multidisciplinary study team will include investigators from general pediatrics and several specialty areas including sleep medicine, endocrinology, ophthalmology, allergy, and otolaryngology. They aim to recruit about 300 patients, with a goal of randomizing 156 participants, from these diverse practice settings.

“I’m hoping we’ll find a nonsurgical alternative for some children but that it also will lead to more personalized medicine,” Dr. Marcus said. “One treatment does not fit all.”

The National Heart, Lung, and Blood Institute is funding the research project.

For more information on the SPARK study, contact research coordinator Ruth Bradford.

Permanent link to this article: http://www.research.chop.edu/blog/new-study-focuses-nasal-steroids-osa-treatment/

Aug 18 2014

Investigating a New Approach to Eosinophilic Esophagitis

Eosinophilic EsophagitisMany of the major milestones in understanding eosinophilic esophagitis (EoE), a food allergy that affects the esophagus, began in research laboratories at The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

Investigators discovered the first gene related to the disease, and they identified an immunological pathway that makes EoE distinctive from other food allergies. Now, they are pursuing a novel approach to cure the chronic disorder, as no medications are approved currently to treat EoE.

“If it works, it can potentially revolutionize clinical care,” said Jonathan Spergel, MD, who is leading the proof-of-concept study called SMILEE.

Dr. Spergel is co-director of CHOP’s Center for Pediatric Eosinophilic Disorders, which treats 1,500 patients with EoE from all over the world. About 70 percent of the patients have milk-induced EoE. When Dr. Spergel first began studying EoE, little was known about the disease, but diagnoses of this disorder are increasing rapidly as awareness grows.

“I have been fascinated to understand exactly who gets EoE, whose at risk, and what’s the best way of treating it,” said Dr. Spergel, who is also chief of CHOP’s allergy section.

During an allergic reaction to a food associated with EoE, high quantities of eosinophils, a type of white blood cell, congregate in the esophagus. This muscular tube that carries food from the throat to the stomach gets swollen. Children with EoE experience varying symptoms including belly pain, trouble swallowing, uncontrollable reflux, and failure to thrive.

Physicians currently approach EoE treatment two ways. First, is avoidance of the food that causes the allergic reaction. Second, is prescription of topical steroids to coat the esophagus. Dr. Spergel pointed out that these options do not address the underlying disease; they only control the symptoms.

“Can we do something better? That’s the question this study is asking,” Dr. Spergel said. “We’re trying to induce tolerance using a novel method — epicutaneous immunotherapy (EPITTM).”

EPIT is a desensitization method developed and patented by DBV Technologies (DBV) and uses Viaskin® technology. The application of a Viaskin per day involves maintaining an allergen on the skin of an allergic person for repeated and prolonged periods. DBV will provide a grant to The Children’s Hospital of Philadelphia to support the clinical trial. DBV and Dr. Spergel designed the double-blind, placebo-controlled, randomized trial to assess the effectiveness and safety of using an investigational new drug intended for EPIT, Viaskin® Milk, an allergen extract of milk administered via a skin patch.

“What we think happens is when the milk is absorbed through the skin, it interacts with antigen-presenting cells, which then induce T regulatory cells, and these T regulatory cells then cause the body not to be allergic anymore,” Dr. Spergel said.

Dr. Spergel anticipates that the SMILEE study will include participants ages 4 to 17. If it turns out that EPIT works, Dr. Spergel said it would be a major turning point for EoE treatment.

“We would be able to completely change the way we treat the disease,” Dr. Spergel said. “All these patients who have been unable to drink milk now would be able to drink milk and improve their quality of life.”

Dr. Spergel has other clinical studies under way of Viaksin® Peanut, another form of EPIT for patients with peanut allergies.

The SMILEE study also is supported by donations from grateful CHOP families.

Permanent link to this article: http://www.research.chop.edu/blog/investigating-new-approach-eosinophilic-esophagitis/

Aug 15 2014

Forced Looping Viable Strategy to Reverse Globin Switch

globinInvestigators at The Children’s Hospital of Philadelphia are exploring a new gene therapy approach that aims to reactivate the production of fetal hemoglobin as a potential intervention for patients with sickle cell disease. In the U.S., it is estimated that sickle cell disease affects 100,000 newborns, especially Hispanic-Americans and African-Americans.

The inherited disease distorts the red blood cells into a sickle shape, like the letter “C,” that blocks blood flow and damages blood vessels and many organs. A sickle cell gene mutation tells the body to make a defective type of hemoglobin, which is the oxygen transport protein in red blood cells.

Pre-empting the effects of this sickle cell gene mutation has been a focus of CHOP hematology researcher Gerd A. Blobel, MD, PhD, and the August edition of Cell reported his novel findings.  Dr. Blobel and his co-authors described how they altered the genetic architecture behind a developmentally controlled process called hemoglobin switching.

A form of hemoglobin that has anti-sickling properties is made only during the fetal period when red blood cells are produced by the liver. Shortly after birth, a transition occurs that silences the fetal globin genes as the bone marrow gradually takes over blood formation. Gene expression shifts to mostly create the adult form of hemoglobin, which in sickle cell disease will be the variant type.

Adult hemoglobin (HbA) almost completely replaces fetal hemoglobin (HbF) within six months after birth, which helps to explain why patients with sickle cell disease do not experience symptoms as newborns. It has been known for a long time that patients with sickle cell disease who have higher ratios of HbF tend to experience a milder course of the disease.

“A major driver in the field for many years has been to understand the molecular basis and the machinery that controls that switch,” Dr. Blobel said. “The goal is ultimately to overcome the silencing of the fetal globin genes and turn them back on.”

His research team’s particular strategy to manipulate gene expression not only elevates the amount of HbF but also downregulates the amount of faulty HbA, thereby reducing the sickle cell inducing properties of the mutated form of HbA.

The current study employs artificial zinc finger protein technology that Dr. Blobel and colleagues adapted for use in hemoglobin regulation and described in Cell two years ago. At the time, the zinc finger proteins were engineered in a way that they locate to specific sites on the chromosomes and foster contacts between chromosomal regulatory elements called promoters and enhancers that reside very far apart on the chromosome. This juxtaposition led to the formation of a chromosomal loop.

“Our 2012 study was the first in which such looped gene contacts were produced at a normal gene in its native location,” Dr. Blobel said. “We thought, now that we have this useful system, let’s explore whether it can be put to therapeutic use.”

In the present study, the researchers showed that they can use forced gene looping to override the stringent developmental gene expression of the globin gene cluster, which is composed of embryonic, fetal, and adult type genes responsible for the creation of hemoglobin. During development, a powerful enhancer for the expression of all these genes, called the locus control region (LCR), physically contacts the embryonic, then fetal, and later the adult genes via chromatin looping.

Dr. Blobel’s team designed zinc fingers in a way that they would promote looped contacts between the LCR and the fetal genes in adult red blood cells. This approach worked well and indeed enhanced the expression of fetal genes and reduced the level of the adult type genes. In the context of sickle cell disease, this would be a double benefit since both high fetal gene expression and low levels of the mutated toxic form of adult hemoglobin would ameliorate the disease.

“This is a novel way to manipulate gene expression via altering chromatin architecture,” Dr. Blobel said.

The researchers carried out the experiments in cultured blood cells from mice and humans. The next step is for the team to use a pre-clinical model to further test their strategy. This involves the use of genetically engineered mice bearing the human globin genes (including the sickle cell anemia gene mutation) in place of the mouse genes. These animals have manifestations of sickle cell disease similar to human patients. Blood stem cells from these mice will be modified with a viral gene transfer vector that expresses the zinc-fingered looping protein, and then used in bone marrow transplants to see if it can correct the disease in the animal model. If this is successful, the long-term goal is to start a clinical trial in humans.

The Sickle Cell Center at CHOP has a longstanding commitment to sickle cell disease research and is one of the largest programs of its kind in the U.S., providing comprehensive care to almost 1,000 patients. Dr. Blobel’s work is supported by funding from the National Institute of Diabetes Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute.

Permanent link to this article: http://www.research.chop.edu/blog/forced-looping-viable-strategy-reverse-globin-switch/

Aug 13 2014

Investigators Explore Safety of Rotavirus Vaccine in NICU

RoatvirusClinicians in neonatal intensive care units across the country are uncertain about when to administer rotavirus vaccination to infants whose medical conditions require prolonged hospital stays, so experts at The Children’s Hospital of Philadelphia conducted a study published in Pediatrics to explore safety concerns that remain unsettled.

Rotavirus (RV) affects nearly all children at some point, often with significant diarrhea. In premature infants it can lead to severe and potentially life-threatening diarrhea and dehydration. Preterm infants are more vulnerable to the infection, in part because they miss the transfer of maternal antibody in the third trimester of pregnancy. In early infancy they are not protected against common forms of rotavirus.

RotaTeq vaccine (RV5), which was developed at CHOP, is effective at preventing rotavirus gastroenteritis, but it must be administered by 104 days of age (14 weeks, six days). Current immunization guidelines state, “preterm infants in NICUs or nurseries who are age-eligible and clinically stable may be immunized at the time of discharge.”

These recommendations put hospitals with large NICUs that often handle complicated cases of prematurity or congenital abnormalities in a time squeeze because they tend to care for babies who must stay in the hospital longer than 104 days.

“We have a population that is at extraordinary risk because they have health problems beyond prematurity and longer lengths of stay, so many would miss out on receiving the vaccine,” said Kelly C. Wade, MD, PhD, MSCE, a neonatologist at CHOP. “We would be discharging babies into the community who don’t have rotavirus protection.”

After careful consideration and discussion, a team of CHOP experts from the Divisions of Neonatology, Infectious Disease, and Pharmacology decided in 2007 to include RV5 with inpatient routine two-month vaccinations to infants receiving some enteral nutrition, also known as tube feeding, regardless of length of NICU hospitalization.

“We believe that the benefit of protecting infants against rotavirus infections outweighs the minimal risk in administering rotavirus vaccine to NICU inpatients,” said Heather M. Monk Bodenstab, PharmD, a CHOP clinical pharmacist. “We are one of very few institutions that actually do this.”

The main reason the American Academy of Pediatrics (AAP) discourages rotavirus vaccination during hospitalization is the possibility that live attenuated virus theoretically could be transmitted to neighboring unvaccinated infants also residing in the NICU. While shedding of attenuated virus has been demonstrated in immunized infants’ stools, Dr. Monk pointed out that symptomatic disease transmission is rare.

Since CHOP’s policy is not in line with the AAP recommendations, Dr. Monk Bodenstab and Dr. Wade conducted the current study in order to give some guidance and build support for the safety of inpatient RV5 vaccination as a CHOP standard of practice. The investigators performed a retrospective chart review of electronic medical records of NICU patients who CHOP routinely vaccinated with RV5 between September 2008 and 2010. They also reviewed records for any unvaccinated patients who shared the same NICU area and nurses as the vaccinated infants within 15 days of vaccination. In particular, the study team wanted to identify any unvaccinated infants who had gastrointestinal symptoms and physician orders for bowel rest, abdominal imaging, and antibiotics within 24 hours of each other, which would suggest a strong clinical suspicion of viral gastroenteritis.

“One of the most interesting findings was that there were such a small percentage of unvaccinated infants who had clinical status changes, and those could be attributed to pre-existing gastrointestinal processes or other clinical conditions,” Dr. Monk Bodenstab said. “That was reassuring for us.”

Due to the study’s design limitations, however, the results do not indicate whether or not RV5 vaccination increased the risk of virus shedding or transmission in a NICU environment. The goal of future prospective studies will be to determine how long a baby who receives the vaccine is potentially shedding the virus, if universal precautions such as diligent hand hygiene can control the spread, and if other infants are exposed, whether or not they become sick.

“None of us has any data to say for sure what would be good practice,” Dr. Wade said. “I think the policy we have at CHOP is well thought out, and it is working for us, but it is not ready for complete dissemination.  We cannot say it is what every NICU should do because you have to factor in different levels of attention to hand hygiene, nurse-to-patient ratios, and room geography.”

Permanent link to this article: http://www.research.chop.edu/blog/investigators-explore-safety-rotavirus-vaccine-nicu/

Aug 11 2014

Celebrating Student Contributions to Injury Research

injury researchA recent event at the Center for Injury Research and Prevention (CIRP) celebrated the wide-ranging accomplishments of a number of students who have been working with CIRP staff and investigators. Held August 5th, the 9th Annual Student Research Day featured presentations that highlighted the scope and breadth of CIRP research, from those focused on teen driving-related topics to concussions to a study of injuries sustained by fans at Major League Baseball venues.

The students in the pediatric research training programs came to CIRP via various programs, including the CHOP Research Institute Summer Scholars Program (CRISSP) and Drexel University’s Co-op program. While many of the students hailed from Philadelphia-area schools — such as the University of Pennsylvania, Temple University, and Villanova University — students from Pennsylvania State University and the University of Kansas also presented.

The day was set up as a sort of “speed-dating” version of a symposium: Each student was given approximately five minutes to talk about his or her research, and at the end of the event a winner of the day’s best presentation was announced, chosen by CIRP investigators Helen Loeb, PhD, and Jessica H. Mirman, PhD. In all, the event featured 11 presentations.

Danielle Cole, a Drexel Co-op student, kicked off the symposium with a discussion of her work on the Cellie Coping Kit. Originally designed to help children and their families manage the physical and emotional challenges associated with cancer treatment, the kit includes its namesake plush toy, a pack of coping cards, and a booklet for caregivers. Over the past few months, Cole helped develop cards for a version of Cellie devoted to injuries, and has been working to raise money to support the project’s development. So far, she has raised $2,500 on her own.

Later in the day, Nicholas Janigian gave a presentation on “Spectator Injuries and Medical Events at MLB Ballparks.” A Villanova University undergraduate, Janigian’s interest in his topic stems from his love of sports and the fact that there is little mention of fan injuries in the scientific literature. Overall, Janigian found that there were approximately 35 instances of fan injuries between 2010 and 2014, including a bizarre case where a fan was blinded by a hot dog shot in the stands by the Kansas City Royals’ mascot Sluggerrr.

And in what turned out to be the day’s winning presentation, Richard Hanna, a BS/MS student at Drexel University, discussed his work improving digital models of child safety restraint systems (CRS). Specifically, Hanna has been using the XBOX Kinect motion detection gaming device to build accurate 3-D models of CRS devices. “CRS designs are in a constant state of flux,” Hanna said, which can lead to confusion and misuse, but having better models can help ameliorate that.

“The Center for Injury Research and Prevention’s annual Student Research Day event offers students the chance to show off their work, and this year was no different. This year’s impressive presentations showed the impact students make during their time at CIRP. We’re so proud of everything they accomplished,” said Carol Murray, MSS, MLSP, the Center’s training manager.

To learn more about the Center for Injury Research and Prevention, and the Center’s pediatric research training programs, visit the CIRP website.

Permanent link to this article: http://www.research.chop.edu/blog/celebrating-student-contributions-injury-research/

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