BenchBedsideRESEARCH AT THE CHILDREN’S HOSPITAL OF PHILADELPHIA September 2009

In the largest study of its kind, pediatric investigators at The Children’s Hospital of Philadelphia have received a federal contract for a project to determine the most beneficial method of using antibiotics to treat urinary tract infections (UTIs) in children. The award, announced Sept. 2 by the National Institute of Allergy and Infectious Diseases (NIAID), aims to answer key questions about the best use of antimicrobial drugs against UTIs, the most common disorder of the kidneys and urinary tract in early childhood. UTIs are highly treatable, but an infection that goes untreated may lead to serious kidney damage. Because widespread antibiotic use has allowed bacteria to evolve strains that are resistant to common drugs, the new study will investigate whether using antibiotics over a shorter period than the standard 10 days is an effective treatment that will reduce the risk of drug resistance. The initial award is for $1.5 million, with total funding of $13.8 million available over the project’s six-year duration if clinical trial milestones are met.

Theoklis Zaoutis, M.D., M.S.C.E., an infectious diseases specialist at the Center for Pediatric Clinical Effectiveness, serves as the principal investigator of the NIAID study. The clinical trial will enroll 700 children at two centers — The Children’s Hospital of Philadelphia and the Children’s Hospital of Pittsburgh. It will be the largest clinical trial to compare a short course versus the standard course of antimicrobial treatments for UTIs in children, says Dr. Zaoutis. “Our goals will be to determine the optimal duration of antimicrobial treatment for UTIs,” he adds. “This information will allow doctors to improve pediatric care while reducing unnecessary use of these drugs.” After an initial period to prepare the trial, Dr. Zaoutis expects to begin enrolling children in 2010.

CHOP Receives Federal Contract to Study Antibiotic Use in Children With Urinary Tract Infections

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In This Issue: l Diabetes Gene Raises Odds of Lower Birth Weight l Eliminating Cell Receptor Prevents Infections in Animal Study l CTRC and IRB Establish Joint Protocol Review Process l Mother’s Immune System May Block Fetal Treatments for Blood Diseases l Revised HIPAA Research Policy Went Into Effect Sept. 1

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Diabetes Gene Raises Odds of Lower Birth WeightPediatric investigators recently found that a gene previously shown to be involved in the development of type 2 diabetes also predisposes children to having a lower birth weight. The finding sheds light on a possible genetic influence on how prenatal events may set the stage for developing diabetes in later childhood or adulthood. Researchers from Children’s Hospital and the University of Pennsylvania School of Medicine published the study July 10 in the online version of the journal Diabetes. “It’s a bit unusual to find a gene linked to both prenatal events and to a disease that occurs later in life,” says study leader Struan F.A. Grant, Ph.D., an investigator with the Hospital’s Center for Applied Genomics. “This gene variant carries a double whammy, in raising the risk of both lower birth weight and the development of type 2 diabetes in later life.” Type 2 diabetes occurs either when the pancreas produces too little insulin or when the body cannot efficiently use the insulin that is produced. Formerly called adult-onset diabetes and still most common in adults, type 2 diabetes has been increasing sharply among children. Grant and study co-leader Hakon Hakonarson, Ph.D., director of the Center for Applied Genomics at Children’s Hospital, investigated 20 gene locations previously reported to be associated with type 2 diabetes. Drawing on a cohort of some 5,700 Caucasian children in an ongoing genome-wide association study of childhood obesity at Children’s Hospital, the researchers compared birth weights with the occurrence of the 20 gene variants. They found that one of the gene variants, called CDKAL1, had a strong association with lower birth weight — a finding that supports the so-called fetal insulin hypothesis. Previous studies by European diabetes researchers, says Dr. Grant, had suggested that CDKAL1 was implicated in both lower birth weight and type 2 diabetes, and the current study, using a large sample size, reinforced that association. Under the fetal insulin hypothesis, a slight underproduction of insulin, an important fetal growth factor, during the prenatal period may cause a baby to be born smaller. Low birth weight is already known to increase the risk of disease later in life, and the fetal insulin hypothesis proposes that the same gene that causes lower birth weight also increases the risk of developing type 2 diabetes. “The mechanisms by which CDKAL1 may act are not well understood, but it is believed to reduce insulin secretion, and that underproduction contributes to type 2 diabetes,” says Dr. Grant. He added that further research may investigate biological pathways on which the gene functions, and may also study whether it may influence the risk of developing other diseases in later life. The National Institutes of Health, the Cotswold Foundation, and The Children’s Hospital of Philadelphia supported this study. Drs. Grant and Hakonarson, and their co-authors, are from both The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine.

New Research Employees (July 2009)

Administrative Fellow Brendan Quinn Clinical Research Assistants Kernika Gupta Anne Hutchinson Clinical Research Coordinator Mary Anne Cornaglia Coordinator – TraumaLink Susan Walker Hospital Negotiator Brooke Janisak NCS Laboratory Research Assistant Donnell Nixon Research Assistant Courtney Brant Research Technicians Amber Bender Anand Bhagwat Mariel Boyd Jacquelyn Bradley Courtney Cheek Sandra Deliard Clara Fajardo Melanie Hullings Erica Koff Benjamin Sawatzky Sanghee Suh Haiyan Xiao Sarah Zelonis Resource Coordinator Jeffrey Olson Social Worker Anthony Davis Visiting Scientist Yue Han

We welcome the following new research employees:

IRB Encouraging Submission at Time of Fundable Score

The Institutional Review Board (IRB) Office is sensitive to the tight timelines related to IRB review of funded grants that involve human subjects research, and is dedicating resources to ensure efficient scheduling for review. The IRB Office encourages you to start your study submission in eIRB as soon as you receive a fundable score. One of the benefits of using the eIRB system is that the status of your submission is visible at all times. Once your eIRB study has been submitted, please also alert the IRB of your submission by e-mailing Amy Schwarzhoff, IRB director, at schwarzhoffa@chop.edu. If you have any questions about using eIRB, please contact the eIRB Help Desk at eIRB@chop.edu or ext. 6-2343.

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Research at Children’s Hospital sheds light on the role of cell receptors in acting as gatekeepers for infectious viruses. By using mice genetically engineered to lack a particular receptor in heart and pancreas cells, the study team prevented infection by a common virus that causes potentially serious diseases in humans. “This finding is a step to understanding how cell receptors operate in infections,” says study leader Jeffrey M. Bergelson, M.D., a pediatric infectious diseases specialist at Children’s Hospital. “Scientists have identified receptors for many viruses that cause disease,” says Dr. Bergelson, “but it is not always clear whether the receptors found in cell cultures actually play a role in the disease process. In this case, we confirmed that this receptor really is involved in the disease.” The current study, published July 23 in Cell Host and Microbe, focused on the coxsackievirus and adenovirus receptor (CAR), which Dr. Bergelson discovered in 1997. He previously found that, in cell culture, Group B coxsackieviruses (CVBs) manipulate cell signals to bind to the CAR. CVBs are common in humans, usually causing minor, transient infections. However, this virus may at times cause potentially severe infections, such as myocarditis in the heart and viral meningitis in the lining of the brain. CVB may also infect the pancreas, causing pancreatitis, and is suspected to contribute to childhood-onset diabetes. Dr. Bergelson noted that his current animal study finding does not have immediate implications for changes in patient care, although discoveries in basic biology often lay the foundation for future clinical treatments in unforeseen ways.

Viruses may have interactions in living organisms that differ greatly from their interactions in cell cultures. They may attack specific tissues in humans or animals, but without binding to the cellular receptors identified in cultured cells. For instance, adenovirus infects the liver, but it bypasses identified adenovirus receptors in that organ. Instead the virus engages in complicated interactions with blood proteins and unidentified molecules in the liver. Therefore, Dr. Bergelson and colleagues set out to discover whether CVB interacts with its receptor to cause pancreatitis and myocarditis in a special breed of mice. By manipulating genes in the pancreas and heart that generate CAR in those organs, Dr. Bergelson’s team prevented the mice from forming CAR at those sites. Subsequently, those mice had virus levels in the pancreas a thousand times smaller than in control animals, and had significantly less tissue damage and inflammation. A similar protective effect occurred in the mice designed to lack CAR in their heart cells. The results indicate that CAR is the receptor used by coxsackieviruses to infect the heart and pancreas and to cause direct injury to tissues. In some patients, recovery from coxsackievirus infection is followed by slowly progressive inflammation and heart damage. Dr. Bergelson’s lab is interested in whether this long-term damage also depends on virus interaction with CAR. Grants from the National Institutes of Health, the American Heart Association, and the ACVP/STP Coalition for Veterinary Pathology Fellows supported this research. Dr. Bergelson’s co-authors were Nicole L. Kallewaard, Ph.D.; Lili Zhang; Jin-Wen Chen, Ph.D.; and Marta Guttenberg, M.D., all from Children’s Hospital; and Melissa D. Sanchez, D.V.M., Ph.D., of the University of Pennsylvania School of Veterinary Medicine.

Eliminating Cell Receptor Prevents Infections in Animal Study

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The Clinical and Translational Research Center (CTRC) provides the resources, environment, operations, and training to support and promote high-quality clinical and translational research by qualified investigators. These resources are now easier to access through a streamlined protocol submission and joint Institutional Review Board (IRB) and CTRC review process facilitated by the eResearch system. Before the streamlined review was established, all CTRC protocols underwent independent review by both the CTRC council and either the Children’s Hospital or Penn IRB. This duplicative and time consuming review process often resulted in conflicting recommendations from scientific reviewers. The joint review significantly shortens and simplifies the process because investigators receive one critique rather than two, which eliminates review conflicts while maintaining high levels of research study oversight. Investigators can now apply for IRB and CTRC review simultaneously. To request CTRC services, Children’s Hospital investigators should first complete eIRB submission in the eResearch system. The eCTRC module is integrated with the eIRB module so that it does not request information that has already been collected.

Investigators should complete the eCTRC application immediately after the eIRB application to ensure a joint protocol review takes place. Submitting requests for eCTRC continuing reviews and amendments follows a similar process. For specific submission instructions, please visit the CTRC’s intranet site at https://intranet.research.chop.edu/display/ctpgctrc/Protocol+Submissions or the Penn Institute for the Translational Medicine and Therapeutics site at http://www.itmat.upenn.edu/ctrc/index.shtml. The CTRC currently assists more than 350 total active research protocols at Children’s Hospital and the University of Pennsylvania Medical Center. Led by Carole Marcus, M.B.B.C.H., at Children’s Hospital and Dan Rader, M.D., at the University of Pennsylvania, it provides core services such as research nursing staff; inpatient and outpatient study visit rooms; research specimen collection, processing, and non-routine assays; nutrition, cardiovascular, pulmonary, sleep, and neurobehavioral services; and biostatistics and informatics support. Some CTRC services are available at low cost and others are provided for free. Contact Sharon Carbonara at ext. 4-0578 or Ronnie Mazzaccaro at ext. 4-2215 if you have questions or would like more information.

CTRC and IRB Establish Joint Protocol Review Process

The Pediatric Research Consortium (PeRC) has released an interactive Web tool that allows users to view information on active clinical research studies conducted in the Hospital’s practice-based research network. Users of the tool can search studies based on attributes such as age range of study participants, study locations, principal investigator, and whether recruitment is occurring or not. Users can then

click on individual studies to obtain more detailed information, including full descriptions. The tool can be found on PeRC’s publicly accessible Web site at http://www.research.chop.edu/cbmi/perc/trialfinder.php. Please direct any questions or comments on this tool to James Massey, PeRC manager, at masseyj@email.chop.edu.

New Web Tool Taps Into Information on PeRC Clinical Research Studies

The Center for Pediatric Clinical Effectiveness (CPCE) has announced Oct. 1 as the deadline for proposal submission for its Pilot Grant Program. The program promotes and supports investigators in clinical effectiveness pilot research studies that will attract external support for larger-scale studies. Investigators from all Hospital departments and divisions, including fellows in their final year of fellowship transitioning to CHOP-affiliated faculty, are encouraged to apply. Selected proposals will be supported for up to a maximum of $10,000 for one year. Projects should be able to be completed within one year. Award announcements will be made Nov. 16.

Studies already in progress or partially funded will not be supported by the Pilot Grant Program, and resubmissions are allowed by invitation only. The CPCE will notify applicants if their submission qualifies to be resubmitted for a future funding cycle. For more details about the application, submission, and review process, please visit the CPCE Web site at http://www.research.chop.edu/programs/cpce/research.php and click on the “Pilot Grant Program” tab. Please e-mail Debbie Hillman, at hillman@email.chop.edu with any questions.

CPCE Announces Oct. 1 Deadline for Pilot Grant Program Submissions

Research at The Children’s Hospital of Philadelphia

Pediatric investigators have resolved an apparent contradiction in the field of prenatal cell transplantation — a medical approach that holds future promise in correcting sickle cell disease and other serious congenital blood disorders. In a new study in animals, the investigators showed that the mother’s immune response interferes with the offspring’s earlier ability to tolerate transplanted donor cells. The study team concludes that focusing on transplant techniques that avoid the maternal immune response may allow scientists to take advantage of fetal tolerance to achieve a long-sought goal of treating blood diseases prenatally. While cautioning that much work must be done to understand how these animal findings apply to humans, the current findings are “surprising but reassuring,” says study leader Alan W. Flake, M.D., of the Children’s Center for Clinical Research. The study appeared online Aug. 3 in the Journal of Clinical Investigation. For more than 50 years, explains Dr. Flake, it has been a fundamental precept of immunology that a fetus tolerates foreign antigens in a window-of-opportunity period before its immune system fully develops the capacity to mount an immune response. Scientists assumed that by carefully introducing donor cells and stimulating a fetus to develop tolerance to those cells, one could set the stage for a later organ or cellular transplant that would not be rejected by a more mature immune system. As prenatal diagnosis has continued to become available for a greater number of congenital diseases, scientists have considered the possibility of correcting blood disorders such as sickle cell disease or thalassemia. After first transplanting a small number of healthy cells in an early-stage fetus to establish tolerance, a second dose of transplanted cells later in gestation would proliferate, and treat the blood disorder before birth. Researchers use hematopoietic cells — stem cells that that develop into blood cells — in this technique, in utero hematopoietic cell transplantation (IUHCT). However, over the years, Dr. Flake’s team and other research groups found that IUHCT studies in animal models yielded inconsistent results, ranging from no tolerance to transplants to full

tolerance and every degree of tolerance in between. Contrary to the concept of fetal tolerance, an immune barrier seemed to be acting against transplanted cells. The current study, done in mice, solves the puzzle of an apparent immune barrier. Newborn mice (pups) that received cell transplants in utero were divided into two groups. Mice nursed by their biological mothers lost the transplanted donor cells, while mice nursed by foster mothers retained those donor cells. The mothers whose fetuses received the donor cell transplants had developed antibodies against those cells, and subsequently transmitted the antibodies to their pups through breast milk. “Those antibodies in the breast milk triggered rejection of the transplanted blood cells in the pups,” says Dr. Flake. “But in the absence of a maternal immune response, we confirmed that immune tolerance does occur in the early-gestation fetus 100 percent of the time.” Of course, mouse biology is not the same as human biology, and Dr. Flake adds, “Mouse time is not the same as human time.” Because mice have such a brief gestational period, the mother’s immune response didn’t develop until after the birth of her pups, and was therefore transferred by breastfeeding. In large animals and humans, says Dr. Flake, the more likely route of maternal-to-fetal transmission would be through the placenta late in pregnancy, and not through postnatal breastfeeding. However, it remains an open question whether the mouse findings are applicable to larger mammals and especially to humans. Dr. Flake’s study team is continuing their investigations in larger animal models. Looking forward to techniques to avoid maternal immune reactions to prenatal cell transplants, Dr. Flake proposes two possibilities. One would be use the mother as a source of donor cells, which would not stimulate an unwanted immune response. Another strategy could involve inducing the generation of increased numbers of T regulatory cells; those cells normally act to prevent the fetus from inappropriately reacting against maternal cells. The ultimate goal, says Dr. Flake, is to develop IUHCT as a prenatal treatment for any congenital blood disorder that may currently be treated with postnatal bone marrow transplants. That would include sickle cell disease, thalassemia, and some inherited immunodeficiency diseases. Currently such postnatal transplants are risky and relatively rare. “Our current finding is not a clinical breakthrough,” adds Dr. Flake. “But it does offer new potential to the field of cellular transplantation.” Funds from the National Institutes of Health, the Ruth and Tristram C. Colket Jr. Chair of Pediatric Surgery at The Children’s Hospital of Philadelphia, and the Albert M. Greenfield Foundation supported this study.

Mother’s Immune System May Block Fetal Treatments for Blood Diseases

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Revised HIPAA Research Policy Went Into Effect Sept. 1The Office of Compliance and Privacy, in collaboration with the Office of Research Compliance and Regulatory Affairs, has launched a new policy, Use and Disclosure of Protected Health Information for Research. As of Sept. 1, this policy replaces, consolidates and clarifies the previous 23 research policies related to the Health Insurance Portability and Accountability Act (HIPAA). The new policy includes significant clarifications related to using and sharing limited data sets, working with coded data, and de-identifying protected health information (PHI). The revisions are designed to improve awareness about HIPAA privacy requirements that impact research and to streamline processes that safeguard the privacy of research participants. To learn more about this new policy and general HIPAA information, investigators are encouraged to attend a scheduled HIPAA training session or request a personalized training for individual research teams.

The Office of Research Compliance and Regulatory Affairs has launched a HIPAA for Research intranet site dedicated to providing information, resources, and training opportunities to the research community. Please visit this site at https://intranet.research.chop.edu /d i sp l ay /dep t comp/HIPAA+and+Res e a rch to view the new policy, training session dates, and other important information. Questions about the Use and Disclosure of Protected Health Information for Research policy may be directed to either Beth Morris Thornton, manager of Privacy Operations in the Office of Compliance and Privacy, at ext. 6-6036 or thorntonb@email.chop.edu; or Amy Schwarzhoff, director of Human Subjects Research in the Office of Research Compliance and Regulatory Affairs, at ext. 6-2346 or schwarzhoffa@chop.edu.

On Sept. 1, 2009, the National Institutes of Health (NIH) began accepting applications for its five Loan Repayment Programs (LRPs) for fiscal year 2010. The five LRPs offered by the NIH include the Clinical Research LRP, Clinical Research LRP for Individuals From Disadvantaged Backgrounds, Contraception and Infertility Research LRP, Health Disparities LRP, and Pediatric Research LRP. Through these programs, the NIH offers to repay up to $35,000 of qualified educational debt annually for health professionals pursuing careers in biomedical and behavioral research. The programs also provide coverage for federal and state tax liabilities. To qualify, applicants must possess a doctoral-level degree; devote 50 percent or more of their time (20 hours

per week based on a 40-hour work week) to research funded by a domestic non-profit organization or federal, state, or local government entity; and have educational loan debt equal to or exceeding 20 percent of their institutional base salary. Applicants must also be U.S. citizens, permanent residents, or U.S. nationals to be eligible. All applications for 2010 awards must be submitted online by 8:00 p.m., Dec. 1, 2009. CHOP’s institutional contact is Bere Saxon, who can be reached at saxonB@email.chop.edu. For an online application, program information, or other assistance, visit the LRP Web site at http://www.lrp.nih.gov/, call 866-849-4047, or send e-mail inquiries to lrp@nih.gov.

NIH Accepting Loan Repayment Program Applications