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In the News: 22q, Mentoring Award, Neonatal E. coli, Gene Therapy, Siegel Award

Published on November 20, 2020 in Cornerstone Blog · Last Updated 2 years 1 month ago


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In the News


By limjr [at] (Jillian Rose Lim)title="E-mail Jillian Rose Lim" and shafere1 [at] (Emily Shafer)title="E-mail Emily Shafer"

Awards and advancements in pediatrics abound in this week’s roundup of research headlines at Children’s Hospital of Philadelphia. Discover how researchers at CHOP are learning more about the causes of behavioral health differences in 22q11.2 deletion syndrome, why new findings support stronger antibiotic stewardship for infants, and meet two CHOP researchers recognized for their mentoring excellence and contributions to children’s health.

Genetic Clues Revealed for Schizophrenia Risk in 22q11.2 Deletion Syndrome

Researchers from the 22q and You Center at CHOP contributed to a study that identified genetic clues that may help identify patients with 22q11.2 deletion syndrome (22q11.2DS) who may be at higher risk for schizophrenia. The findings appeared in Nature Medicine.

The researchers used genetic data from the International 22q11.2 Brain and Behavior Consortium (IBBC), which is led by CHOP and the Perelman School of Medicine at the University of Pennsylvania. They analyzed 965 patients with 22q11.2DS to evaluate genetic associations by using polygenic risk scores for schizophrenia and cognitive ability. The findings indicate that polygenic risk scores play an important role in assessing the likelihood of a patient developing schizophrenia or cognitive decline.

“This work is an important next step in better understanding the causes of behavioral health differences associated with 22q11.2 deletion,” said co-author Donna McDonald-McGinn, MS, LCGC, director of the 22q and You Center, associate director of Clinical Genetics, and chief of the Section of Genetic Counseling at CHOP, and clinical professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine.

Learn more about the study in the CHOP press release.

Penn’s Outstanding Faculty Mentoring Award Recognizes Matthew Weitzman, PhD

Congratulations are in order for Matthew Weitzman, PhD, co-director of the Division of Protective Immunity at CHOP, for his receipt of the 2020 Arthur K. Ashbury Outstanding Faculty Mentoring Award. The award recognizes a faculty member who has fostered the professional development of other faculty members by offering inspiring and effective counsel and opportunities for achievement. The award recipient “establishes a supportive and nurturing relationship with other faculty members and helps them to negotiate the complex demands of academic life, improve their skills and opportunities, and reconcile the competing claims of work and home life,” according to the Perelman School of Medicine.

At CHOP, Dr. Weitzman also has been recognized as an incredible mentor to our postdocs and research fellows, having received the Award for Excellence in Mentoring Research Trainees. Dr. Weitzman’s wide-ranging contributions include advancements in the fields of virology and DNA repair, as well as the initiation of Grant Proposal Success (GPS) groups across CHOP and Penn. These groups, which over 250 trainees and Penn faculty have been involved, offer a community-based opportunity to learn effective grant-writing skills through peer review, mentorship, and more.

Learn more about the Faculty Mentoring Award and Dr. Weitzman’s research at CHOP.

New Study Finds Significant Proportion of Neonatal E. coli Infections Resistant to Common Antibiotics

A new analysis published in JAMA Pediatrics reports that a substantial portion of neonatal E. coli infections are resistant to commonly used antibiotics — a finding that may help to inform empirical antibiotic prescribing for newborns across the U.S. Dustin Flannery, DO, MSCE, attending neonatologist at CHOP Newborn Care, and his colleagues collected isolates from 721 infants with E. coli infections across the country between 2009 to 2017. The team found that among 218 infants with early-onset infection, 22 (or 10.1%) had isolates with nonsusceptibility to both ampicillin and gentamicin, the antibiotics most commonly administered to newborns.

The results support guidelines from the American Academy of Pediatrics Committee for managing neonatal early-onset sepsis, which recommends the empiric use of combined ampicillin and gentamicin for term and preterm infants at risk. However, Dr. Flannery said the results also emphasize the need to consider broader spectrum agents for critically-ill infants at the highest risk of infection and continue surveillance of antibiotic susceptibility patterns over time.

“We performed this study because E coli is one of the most common pathogens infecting newborn infants, [and] there are reports of increasing gram-negative resistance in other settings,” Dr. Flannery told Contagion Live, where the research was recently featured. “We need to closely follow neonatal E coli antibiotic susceptibility patterns to ensure we are choosing optimal empiric antibiotic regimens for newborn infants while awaiting culture results.”

Read the study abstract.

American Pediatric Society Honors Lisa Young, MD

The American Pediatric Society (APS) named our own Lisa R. Young, MD, chief of the Division of Pulmonary and Sleep Medicine, as the 2021 recipient of their Norman J. Siegel Outstanding Science Award, highlighting Dr. Young’s “considerable contributions to pediatric science.” The award, which honors one of the world’s leading nephrologists, Norman J. Siegel, will be presented to Dr. Young May 3 during the APS Presidential Plenary at the Pediatric Academic Societies 2021 Virtual Meeting. Dr. Young’s research addresses the mechanisms underlying the pathology of interstitial and rare lung diseases and aims to develop new strategies to treat these disorders. 

“Dr. Young has clearly demonstrated outstanding levels of high achievement in clinical care, research, education and training,” said Steve Abman, MD, APS president, in a press release. “Most impressively, Dr. Young has driven key collaborative efforts through the children’s Interstitial Lung Disease (chILD) research network, a national network of multidisciplinary clinicians and investigators. Her work has already led to a greater understanding of these diseases that will lead to novel diagnostic and treatment strategies for rare lung diseases. As a newly elected member of the society, we are truly honored to count her among our distinguished child health leaders.”

Learn more in the press release.

New Study Finds Further Research Needed to Assess AAV Gene Therapy’s Long-term Safety

In a decade-long study working with adeno-associated (AAV) gene therapy in hemophilia A dogs, researchers reported that the gene therapy was successful in significantly improving the bleeding disorder in the animals, but they also detected integrations throughout the genome with evidence of clonal expansion in genes associated with cell growth and cancer in humans. Though they found no signs of cancer in the animal models, the researchers believe the genomic changes represent potential safety concerns that warrant further research and highlight the importance of long-term monitoring of patients treated with AAV vectors.

In a new paper published in Nature Biotechnology by a research team led by Denise Sabatino, PhD, investigator in the Division of Hematology, the study team suggests more research is necessary to determine whether AAV gene therapy might promote cancer in rare instances. AAV is a natural virus engineered to deliver therapeutic genes into the cells of patients with genetic diseases like hemophilia. Though AAV vectors do not usually insert their own genomes into those of the patient, the researchers found genomic changes in the animal models that may increase the risk of liver cancer. In this study, the therapeutic gene delivered via the AAV vector synthesized a protein called coagulation factor VIII, which the team found resulted in the synthesis of the factor VIII for up to 10 years showing that the treatment can be sustained long term. 

Learn more and read the study abstract.

Precise Treatment Targets Genetic Pathway and Resolves Patient’s Debilitating Symptoms

Researchers identified a genetic mutation along a pathway related to lymphatic vessel development and function and used an existing drug to target the pathway that resolved a severe lymphatic disorder in a girl with Noonan Syndrome.

“This study is quite significant,” said first author Yoav Dori, MD, PhD, director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP. “Inhibiting this pathway seems to have sweeping, widespread effects on the lymphatic system. How this process occurs is not fully understood, but is remarkable in its speed and breadth. This gives us a lot of hope for treating other patients with genetic mutations along this same pathway in the future.”

Based on whole exome sequencing done at CHOP’s Center for Applied Genomics, the research team learned that the patient had a genetic mutation in the SOS1 gene, which operates along the RAS-MAPK pathway. This pathway involves mitogen-activated protein kinase (MEK), and the mutation caused an overproduction of MEK, which resulted in the uncontrolled proliferation of her lymphatic vessels.

The research team had previously used a MEK inhibitor, trametinib, in another patient with a severe lymphatic disorder with great success. That patient had a mutation in the ARAF gene, which is also on the RAS-MAPK pathway. Although the SOS1 mutation is distinctly different than the ARAF mutation seen in the other patient, the drug was equally effective because it targets and blocks the function of MEK. The case study published today in Pediatrics described a resolution of the girl’s symptoms within three months while on the medication.

“This discovery is extremely important because Noonan Syndrome has the biggest patient population with alterations in MEK signaling,” said Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics and co-author of the paper. “Not all Noonan patients will have mutations that respond to this therapy, but a very good number of them will.”

Read more details about this innovative approach and the girl’s story in the press release.


Catch up on our headlines from our Nov. 6 In the News:

  • COVID-19 Cases Projected to Increase Over Next Four Weeks
  • Early Tracheostomy Tube Change is Safe, Leads to Fewer Complications
  • Ortho Chief Named Vice President of ABOS
  • CHOP Rheumatologist Recognized by American College of Rheumatology
  • Researchers Identify Spectrum of Musculoskeletal Pain Among Children

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