Bench to Bedside

July 2013

CHOP Research Announces New DNA-Protein Interaction Affinity Group


Since the completion of the Human Genome Project, there has been a natural surge in biomedical research aimed at gene discovery. Using genome-wide association studies (GWAS), bioinformatics, and other approaches, this process has focused largely on determining what genes are implicated in specific diseases.

While this process may shed light on what genes are involved in diseases, it has done little to help investigators understand why a gene or genomic region may be involved in a disease or a disease risk.

A new Research Affinity Group at CHOP Research aims to take the findings from various types of studies, including GWAS, a step further in order to understand entire networks underpinning disease susceptibility.

At the heart of the DNA-Protein Interaction Research Affinity Group is the analysis of data derived from chromatin immunoprecipitation coupled with high-throughput sequencing. More commonly referred to as ChIP-seq, the technique is used to look at how proteins like transcription factors interact with DNA, and to find the regions of the genome these transcription factors occupy to control gene expression.

The DNA-Protein Interaction research affinity group, co-led by Struan Grant, PhD, of the Department of Pediatrics and Genetics, and Andrew Wells, PhD, of the Department of Pathology, will deal with the processing and analyses of ChIP-seq and related data to gain insight into disease networks, identify vulnerabilities in given networks, and look for points amenable to therapeutic intervention.

“The new affinity group is a forum for investigators with diverse backgrounds and expertise to learn the downstream effect of transcription factors and related DNA binding proteins,” says Dr. Grant. “We can now work to analyze and translate the numerous findings made from GWAS and elsewhere — a natural step in discovering not only what causes disease but why.”

Also relevant to the goal of the affinity group is leveraging the data from the public research consortium ENCODE — the Encyclopedia Of DNA Elements — to better understand and integrate genome-wide data sets generated by investigators at CHOP. Launched by the National Human Genome Research Institute nearly a decade ago, the ENCODE project aims to ultimately identify all functional elements in the human genome sequence.

“The sequencing of genomic information is not the bottleneck — it’s the analysis,” says Dr. Wells. “The DNA-Protein Interaction affinity group creates a community that can benefit from what we can learn about disease networks through ChIP-seq and related techniques, and then develop a pipeline to find novel ways to understand and target those diseases.

Investigators interested in joining the new affinity group should contact Struan Grant and Andrew Wells.

The Research Affinity Group structure at the Research Institute builds upon areas of existing strength, identifies new and important research areas, and explores important, broad, and interdisciplinary scientific questions that may have an impact on the health of children. Investigators collaborate across disciplines more easily to address issues of central importance to children’s health. This collaboration has the potential to link multi-talented investigators with common research interests who are widely dispersed through the Institute.

For more information on other Research Affinity Groups at CHOP Research, please visit the Institute’s website.

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Using Capsid Decoys to Divert Antibodies from Neutralizing Gene Therapy


Gene therapy researchers at The Children’s Hospital of Philadelphia have produced a bioengineered decoy that by fooling the immune system prevents it from undermining benefits delivered by a corrective gene. The decoy, which proved effective in animal studies, could offer a new treatment for genetic diseases such as hemophilia while advancing the broader field of gene therapy if the approach succeeds in humans.

“This decoy strategy could be individualized to patients and could greatly expand the population of patients who may benefit from gene therapy,” said the study’s leader, Katherine A. High, MD, director of Children’s Hospital’s Center for Cellular and Molecular Therapeutics (CCMT). “Right now, 30 to 60 percent of adult patients develop antibodies that block the ability of an intravenously infused vector to reach the target cells in the liver. This approach holds the promise of overcoming this roadblock — pre-existing antibodies — and allowing successful intravenous gene therapy in virtually all adult patients.”

Dr. High and co-corresponding author Federico Mingozzi, PhD, formerly of Children’s Hospital, recently published their study in Science Translational Medicine. Dr. High, who is also a Howard Hughes Medical Institute Investigator, has led pioneering investigations of gene therapy at Children’s Hospital for the inherited bleeding disorder hemophilia and other diseases.

In earlier clinical trials, Dr. High used adeno-associated virus (AAV) as a vector to ferry a corrective DNA sequence to patients with a mutation causing hemophilia B, the second most common form of the disease. The delivered gene enables the patient to produce a needed blood-clotting factor.

AAV does not cause human disease, but because we are routinely exposed to this virus, 30 to 60 percent of people develop antibodies that neutralize AAV if it enters the circulation. To extend the potential benefits of gene therapy to a broader population, researchers have long sought ways to better manage this immune response. The decoy strategy could solve this challenge for any disease in which vectors must be delivered through the circulation.

In the current study, Dr. High and her team investigated capsids, the protein shells that surround viruses. Following in vitro studies in human serum, the researchers injected empty AAV capsids along with gene therapy vectors into a mouse model. The anti-AAV neutralizing antibodies bound to the capsid decoys, allowing the DNA-carrying vectors to evade the antibodies and enter the targeted cells in the liver.

The study team next engineered the capsids to disable their ability to enter target cells. This prevented the capsids from triggering a second immune response, from T cells, that also could eliminate the corrective genes. The gene therapy was safe and effective in rhesus macaque monkeys, which produced higher levels of clotting factor, with no adverse effects.

“Our results, which held up over a range of doses, suggest that in clinical studies, it will be feasible to adjust the ratio of empty capsids to gene vector doses, depending on an individual’s pre-existing level of neutralizing antibodies,” said Dr. High. “That means we could personalize gene therapy to make it more efficient for each patient.”

“This work should make it possible to bring effective gene therapy to most adults with severe hemophilia B,” Dr. High added. “Each patient would receive a personalized final formulation that contains just the right amount of empty capsid to neutralize any pre-existing antibody, and allow the gene-expressing vector to reach the liver.”

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CHOP Cancer Experts Awarded Alex’s Lemonade Stand Grants


As part of its mission to find “a cure for all children with cancer,” Alex’s Lemonade Stand Foundation recently announced more than $7 million in new grants to researchers around the country, including four at The Children’s Hospital of Philadelphia. Children’s Hospital investigators Garrett Brodeur, MD, Michael Hogarty, MD, Richard Aplenc, MD, and Robert Schnepp, MD, PhD, all received grants from the organization, for a total of $800,000 in cancer research funding.

Originally started in 2000 by then 4-year-old Alexandra “Alex” Scott (1996-2004) as a lemonade stand to raise money for cancer research, over the years Alex’s Lemonade Stand Foundation (ALSF) has evolved into a robust national organization. Since its inception, ALSF has raised more than $60 million to fund over 300 groundbreaking research projects. The foundation has had a close relationship with Children’s Hospital since 2001, when the Scott family moved to the Philadelphia area so Alex’s neuroblastoma could be treated at CHOP.

The recent ALSF grants fell into three categories: Innovation Awards, Young Investigator Awards, and Epidemiology Awards. Drs. Brodeur and Hogarty each received Innovation Awards, which “provide critical and significant seed funding for experienced investigators with a novel and promising approach to finding causes and cures for childhood cancers.” Innovation award grantees receive $250,000 over two years.

Dr. Brodeur’s award will fund his investigation of using nanoparticles to deliver therapeutic agents. “In an era of extremely tight funding from the NIH, this grant is HUGE for us to continue some very exciting work on targeted nanoparticle delivery of conventional chemotherapy to both increase efficacy and decrease toxicity,” Dr. Brodeur said. “We are confident that this work will lead to longer term funding and a clinical trial, with the preliminary data made possible by ALSF.”

For his part, Dr. Hogarty will study the epigenetics of the childhood cancer neuroblastoma. Often appearing as a solid tumor in a child’s chest or abdomen, neuroblastoma is one of the deadliest pediatric cancers, causing 10 to 15 percent of all cancer-related deaths despite only comprising 7 percent of childhood cancers.

Dr. Aplenc, meanwhile, was the recipient of an Epidemiology Award, and will receive $200,000 over two years. The grant will support a project that seeks to “improve the effectiveness of cooperative use trials by using administrative clinical data from approximately 100 hospital sites.” By merging data from several sources, Dr. Aplenc and his team will be able “to study resource utilization questions that previously could not be studied and will allow estimation of inpatient hospital costs” associated with clinical trial treatment regimens, he said.

And last but not least, Dr. Schnepp received a Young Investigator Award, one “designed to fill the critical need for start up funds for new researchers and physicians to pursue promising research ideas.” Currently an instructor and attending physician working in the laboratory of John M. Maris, MD, Dr. Schnepp has been investigating what role the protein LIN28B plays in neuroblastoma.

Saying that he was “extremely grateful” for the $100,000, two-year ALSF grant, Dr. Schnepp noted “this funding will allow us to continue our efforts to understand how LIN28B, a gene that promotes neuroblastoma, actually carries out its cancer-promoting function.”

“We will do our utmost to better understand how LIN28B functions, with the ultimate aim of improving treatment for neuroblastoma and perhaps other cancers,” he added.

To read more about the recent grants, see the Alex’s Lemonade Stand Foundation grants page. For more information on cancer care at CHOP, see the Cancer Center.

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Duke Researcher, CHOP Alum Named Physician-in-Chief


Noted microbiologist and Children’s Hospital alumnus Joseph W. St. Geme, III, MD, was recently named CHOP’s Physician-in-Chief and Chair of the Department of Pediatrics at the University of Pennsylvania. Dr. St. Geme, who officially started July 1, succeeds long-serving CHOP veteran Alan R. Cohen, MD, who held the post of Physician-in-Chief for 12 years.

After receiving his medical degree from Harvard, Dr. St. Geme served his residency and chief residency at Children’s Hospital from 1984-88. After his time at CHOP, he performed postdoctoral research under Stanley Falkow, PhD, at Stanford, and in 1992 joined the faculty of the School of Medicine at Washington University in St. Louis. A progression of appointments followed, and in 2005 Dr. St. Geme moved to Duke University, where he served as chairman of the Department of Pediatrics and Chief Medical Officer of Duke Children’s Hospital.

Dr. St. Geme studies host-pathogen interactions, and much of his work has been focused on examining the bacterium Haemophilus influenzae. Despite its name, H. influenzae does not cause influenza, but is instead associated with invasive infections and localized respiratory tract disease.

More recently, Dr. St. Geme has also been investigating Kingella kingae, an emerging cause of bone and joint infections in young children. Earlier this year he led a study published in the Journal of Bacteriology that examined calcium binding in two K. kingae-associated proteins, PilC1 and PilC2. The study demonstrates “the importance of calcium binding in controlling Kingella pilus-mediated adherence, broadening earlier reports regarding the PilC family of proteins and raising the possibility that the PilC family of proteins may be targets for novel antimicrobials,” Dr. St. Geme said.

Ultimately, Dr. St. Geme said his “great respect” and fondness for CHOP led him to return to the Philadelphia area. He called the opportunity to serve at the site of his medical training “very appealing and ultimately irresistible.”

Saying he was “very pleased” that Dr. St. Geme had agreed to join CHOP, Children’s Hospital’s CEO Steven M. Altschuler, MD, noted he is “a distinguished researcher and member of the Institute of Medicine and is recognized nationally for his outstanding leadership at Duke.”

“In many respects CHOP sets the standard in pediatrics as a leading children’s hospital nationally and internationally, and I’m excited to participate in establishing the standards in pediatric clinical care, education, and research as a member of the CHOP community,” Dr. St. Geme said.

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Health Services Expert Jeffrey H. Silber, MD, PhD, Named to New Endowed Chair


Pediatrician and healthcare economist Jeffrey H. Silber, MD, PhD has been named the first Nancy Abramson Wolfson Endowed Chair in Health Services Research at The Children’s Hospital of Philadelphia. Currently Director of The Children’s Hospital of Philadelphia’s Center for Outcomes Research, Dr. Silber is an authority on outcomes measurement and severity of illness adjustment.

Since its inception in 1988, the Hospital’s Endowed Chair program has supported pioneering investigators working to understand and treat childhood diseases. Named for an honoree, endowed chairs currently provide crucial, assured funding to more than 100 CHOP researchers.

The new Endowed Chair is named for longtime Children’s Hospital Board of Trustees member Nancy Abramson Wolfson, who has served as the chair of the Hospital’s annual fundraising Daisy Day Luncheon for the past 15 years. Over the years, the luncheon has raised more than $14 million to support care and research at CHOP, and the 2013 Daisy Day Luncheon raised more than $1.5 million to support Children’s Hospital’s Pain Management Program. The Endowed Chair was created to honor Nancy Abramson Wolfson’s contributions, and to ensure that the Hospital will be able to continue to recruit and support top researchers and pediatricians like Dr. Silber.

After receiving his MD from Johns Hopkins School of Medicine, and completing his Pediatrics Residency at the Johns Hopkins Hospital, Dr. Silber joined the University of Pennsylvania, where he studied economics and began working in cancer survivorship in CHOP’s Division of Oncology. He completed his hematology/oncology fellowship at CHOP in 1988, and received his PhD in Health Care Management from The Wharton School in 1990. In 1989 he became an assistant professor in CHOP and Penn’s Division of Pediatric Oncology, eventually earning the rank of Professor in 2004. In addition to his role at CHOP, Dr. Silber is also professor of Health Care Management at the Wharton School.

In 1990 Dr. Silber created the Failure-to-Rescue metric, which has since been adopted by numerous groups interested in measuring hospital quality of care, including being endorsed by the National Quality Forum. He has published extensively on the use of multivariate matching in healthcare, and has applied this approach to problems in both pediatric and adult medicine and surgery, disparities research, and cancer. Dr. Silber has twice been awarded the Article of the Year Award in Health Services Research from AcademyHealth, the leading professional organization concerning Health Services Research in the U.S.

In addition, since 1997 Dr. Silber has directed CHOP’s Center for Outcomes Research, which aims to improve health outcomes through the development, testing, and application of innovative, practical metrics that serve as tools to transform the quality and efficiency of health care. Dr. Silber has been the principal investigator on numerous federal grants involving health services research, including recent support to CHOP as one of seven Centers of Excellence by the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality for advancing the field of pediatric quality assessment through the national Pediatric Quality Measures Program.

To learn more about the work being done at the Center for Outcomes Research, see the Center’s website.

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Penn Team Finds Immune Cells Promote Food-Allergy Associated Inflammation


According to the CDC, approximately 4 to 6 percent of U.S. children under the age of 18 have food allergies. Food allergies can lead to a range of symptoms, from hives to abdominal cramps to serious, life-threating conditions like anaphylaxis. Unfortunately, there is no cure for food allergies, and the best treatment for many patients is simply to avoid certain foods.

But a new study could offer hope for those with food allergies. A team from the Perelman School of Medicine at the University of Pennsylvania recently published a study in Nature Medicine that sheds light on food allergy-associated inflammation. Led by David Artis, PhD, the team examined eosinophilic esophagitis (EoE), a food allergy-associated disease affecting children and adults caused by inflammation in response to certain foods, such as eggs or soy. The inflammation associated with EoE can lead to esophageal dysfunction, painful digestion, and weight loss. Current treatment options involve adherence to strict diets.

Several Children’s Hospital investigators also contributed to the study, including Director of the Center for Applied Genomics Hakon Hakonarson, MD, PhD, Patrick M.A. Sleiman, PhD, Terri F. Brown-Whitehorn, MD, and allergy expert Jonathan Spergel, MD, PhD.

With their study, Dr. Artis and his colleagues sought to better understand the condition’s underlying mechanisms. Using a mouse model, they showed that a rare type of immune cells known as basophils promote EoE when coupled with a sensitivity to egg and peanut protein and increased levels of thymic stromal lymphopoietin (TSLP), a protein produced by epithelial cells in the esophagus.

Dr. Artis’ recent study builds on previous work by CHOP investigators. In 2010, Drs. Sleiman and Hakonarson  — along with Struan F.A. Grant, PhD, associate director of the Center for Applied Genomic, and Drs. Spergel and Brown-Whitehorn — published a study in Nature Genetics that found EoE was associated with TSLP.

“The use of this new mouse model has revealed that TSLP production, and the resulting basophil responses, may be critical in promoting EoE in response to exposure to allergy-triggering foods,” said Mario Noti, PhD, one of the study’s co-authors and a postdoctoral researcher in Dr. Artis’s lab.

The study will help researchers better understand eosinophilic esophagitis, and could eventually be used to develop targeted therapeutics to treat the condition, the researchers say.

“Although more research is required, these studies suggest that we may be able to target TSLP and basophils to treat esophageal inflammation associated with EoE,” Dr. Artis noted.

To read more about this study, see the full press release from Penn Medicine.

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CHOP Immune Therapy Trial Highlighted by Association of American Medical Colleges


On its research advocacy blog Research Means Hope, the Association of American Medical Colleges (AAMC) recently highlighted an innovative immune therapy trial led by researchers from CHOP and Penn that led to the dramatic recovery of one young patient. Before being treated with bioengineered T cells that were designed to destroy cancer cells, the prospects for Emily Whitehead were grim: her leukemia had relapsed, and conventional treatments had proven ineffective. However, after being treated with immune therapy at Children’s Hospital, Emily achieved a complete response, and remains cancer-free to this day.

The trial was featured as part of the AAMC’s Research Means Hope campaign, which seeks “to raise public awareness of the critical need for sustained federal funding for medical research” from the NIH, according to the AAMC’s page. The campaign was launched to underscore how “cutting funding to medical research will have dire consequences for the quality of healthcare in the future and the development of life-saving medical advances.” Because of sequestration, the NIH is required to cut $1.55 billion or 5 percent of its 2013 budget, which could lead to approximately 700 fewer grants issued and delays in medical progress, according to the NIH’s website.

Emily’s inspirational story was shared on the new “Bench to Bedside” section of Research Means Hope (coincidentally, Bench to Bedside is also the title of CHOP Research’s monthly publication). “I think Emily’s story shows how important it is to fund medical research,” said her mother, Kari Whitehead. “We need to provide funding to help other children like Emily. If it weren’t for this medical research, we wouldn’t be parents now.”

To read more, see Research Means Hope!

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Cancer Researcher, Core Technician Named Research Administration Fellows


The Office of Postdoctoral Affairs recently announced the selection of two new research administration fellows. Radhika Iyer, PhD, a research associate in the lab of pediatric cancer expert Garrett Brodeur, MD, and Christian Mercado, MS, a technician in the Nucleic Acid / Protein Research core facility, began their fellowships in early July.

The Research Administration Fellowship is a part-time, unpaid, six-month program that fellows complete concurrently with their research duties. The overall goal of the fellowship is to provide the fellow with a broad overview of CHOP Research Administration through rotations with administrative directors in the fellows’ areas of interest.

After receiving her doctorate in molecular and cellular biology from Ohio University in 2006, Dr. Iyer joined Dr. Brodeur’s laboratory. Dr. Iyer has assisting Dr. Brodeur in his investigation of receptor tyrosine kinases (TRK), a family of signaling proteins. Dr. Brodeur has been working with TRK inhibitors to treat neuroblastoma, an often-complex solid cancer that causes 10 to 15 percent of all childhood cancer-related deaths. Dr. Iyer has also been studying the possibility that nanoparticles could be used to deliver drugs to treat childhood cancers.

The Research Administration Fellowship “will provide me with the opportunity to learn the administrative aspect of establishing a successful research lab as well as the details that go into the managing a successful research institute,” Dr. Iyer said.

The second new Research Administration Fellow is Christian Mercado, a senior technical specialist in the Nucleic Acid / Protein Research (NAP) core facility. The NAP core “provides a centralized source for specialized services, technical expertise and reagents to support investigators’ molecular biology research needs.” Services provided by the core include DNA sequencing analysis, microarray services, denaturing high-performance liquid chromatography, and RNA analysis.

After receiving his Bachelor’s from Penn State, Christian went on to earn his Master’s of Science in Biotechnology from Drexel University in 2008. Christian, who first came to CHOP in 2007, is currently working toward his MBA and Master’s of Science in Finance at Drexel.

During his time as a Research Administration Fellow, Christian hopes to “learn how the research institute works as a business.” Because the Research Institute is quite large — comprising approximately more than 500 investigators and a staff in the thousands — he is also interested in learning more about how “the different admin groups accomplish their goals and cooperate with one another.” Overall, Christian said that he hopes to take on a project that will benefit the Institute during his fellowship.

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Lisa Speicher, PhD, Leaves CHOP for Penn


Lisa Speicher, PhD, recently decided to leave her position at Children’s Hospital to assume an exciting new role as the Executive Director of the Office of Clinical Research at the University of Pennsylvania School of Medicine.

While at CHOP, Lisa oversaw tremendous growth in the Clinical Trials Office (CTO), for which she served as director since 2006. She also spearheaded the development of the Office of IND/IDE Support and served as its director, and was associate director of the Office of Clinical and Translational Research.

Lisa’s official last day at CHOP was July 19. Jennifer Goldfarb will serve as interim director of the CTO, and questions and issues related to clinical trials should be directed to her. Questions about IND/IDE Support should be directed to Mary Leonard.

While we are sorry to lose her, we are excited for the new opportunity for Lisa to bring her extensive talents and expertise to our colleagues at Penn.

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