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Advancing Gene Therapy, CSF Tests, Managing Vascular Anomalies, New Clinical Futures Director

Published on August 9, 2019 in Cornerstone Blog · Last updated 4 months ago


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The cicadas may be “singing,” but the summer season isn’t over quite yet. In the midst of heat waves, drenching rainstorms, and vacation escapes, our investigators continue to advance scientific discovery. In this edition of In The News, Children’s Hospital of Philadelphia researchers report a more sensitive method of detecting genetic material delivered via adeno-associated viral vectors, while another group published findings that could help avoid unnecessary non-culture cerebrospinal fluid infection tests. Meanwhile, Petar Mamula, MD, looks into more effective management of a rare vascular anomaly, and Alex Fiks, MD, assumes a director role within the Research Institute. 

CHOP Researchers Continue Gene Therapy Advancements

Continuing their work of developing adeno-associated viral (AAV) vectors as a groundbreaking clinical tool for gene therapy and gene editing, Children’s Hospital of Philadelphia researchers now report a more sensitive method for capturing the footprint of AAV vectors—a broad range of sites where the vectors transfer genetic material. By capturing the full range of gene expression patterns caused by adeno-associated viral vectors, the technique is expected to advance the already rapidly evolving field of gene therapy. The innovative results were published July 30 in Nature Communications.

AAV vectors are bioengineered tools that use a harmless virus to transport modified genetic material safely into tissues and cells affected by difficult-to-treat conditions. These vectors deliver modified genes that will create new instructions for those tissues and help treat disease. 

For safe and effective application of these vectors, researchers must have a complete picture of where the virus delivers its genetic cargo in the body. Conventional methods to define gene transfer rely on fluorescent reporter genes that glow under a microscope, highlighting cells that take up and express the delivered genetic material. However, these methods reveal only cells with stable, high levels of the modified genetic material. The novel technology described in this study enables better detection of where the cargo is expressed, even if it is at extremely low levels or only for a short time.

“Conventional screening methods miss transient or very low levels of expression from AAV viral vectors,” said study leader Beverly Davidson, PhD, chief scientific strategy officer at CHOP and director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics. “What this study shows is that AAV vectors lead to gene transfer in many more places than we and other groups initially realized.”

Read the complete press release.

Does Your Patient Really Need That CSF Test?

A new study from CHOP researchers in neurologyinfectious disease and ophthalmology found that non-culture cerebrospinal fluid (CSF) infection tests were frequently ordered on children with healthy immune systems who underwent lumbar puncture, even when they had normal CSF white and red blood cell counts. In addition, positive results in these children were rare and unlikely to be independently associated with their clinical care. The researchers, whose findings were published in JAMA Network Open, concluded that delaying the decision to send non-culture CSF infection tests until CSF cell counts are available could reduce unnecessary diagnostic testing and medical costs, which may improve value-based care.

Jennifer McGuire, MD, a pediatric neurologist in the Division of Neurology at CHOP, and colleagues studied the records of more than 4,000 children with healthy immune systems between 6 months and 18 years of age and who underwent a spinal tap at CHOP. Sixty-nine percent (1,270) of the children had normal cell counts, yet still received at least one non-culture CSF infection test, such as polymerase chain reaction and antigen or antibody assays, each of which are used to identify specific pathogens in suspected central nervous system infections. The researchers suggested this may happen because clinicians do not always wait to see CSF cell count results before ordering additional testing.

The study team found that 18 of those 1,270 lumbar puncture specimens with normal cell counts had a positive non-culture infection test, and of those 18 children, 2 required clinical intervention; but each of those patients also had other clear clinical signs of infection.

“This current study demonstrates that the yield of sending non-culture CSF infection testing on spinal fluid from children with healthy immune systems and normal CSF cell counts is very low,” McGuire said. “Rather than order these tests across the board, we hope these data help clinicians take a more nuanced approach to testing. Delaying the decision to send these tests until CSF cell counts are available, unless they have a specific, active clinical concern for an infection, could dramatically improve value-based care.”

Exploring Successful Management of a Rare Vascular Anomaly

Petar Mamula, MD, director of the Kohl's GI Nutrition and Diagnostic Center at Children's Hospital of Philadelphia, and co-director of the Joint Penn-CHOP Center for Digestive, Liver and Pancreatic Medicine, is co-author of a study published July 26 in Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. The multicenter, retrospective study analyzes a case series of pediatric patients with Blue Rubber Bleb Nevus Syndrome (BRBNS), a rare, sporadically occurring disorder characterized by multiple venous malformations. The researchers aimed to explore diagnostic approaches and options for managing the condition.

Eighteen patients diagnosed with BRBNS were included with cutaneous venous malformations observed in 78 percent of patients and gastrointestinal venous malformations in 89 percent. In addition, lesions were found in organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys, and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. 

Findings showed the management of the condition varied significantly among treatment centers, and that endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and patients with musculoskeletal or other organ involvement, the immunosuppressant sirolimus was used with 100 percent success rate in the reported series of 5 patients, although poor compliance with trough levels led to recurrence in a minority of patients.

Diagnosis and management of patients with BRBNS require a multidisciplinary approach by nature of its multiorgan involvement. While treatment currently includes conservative, medical, endoscopic, and surgical options, the authors concluded that prospective multicenter studies are needed to identify the optimal management of this rare condition.

Alex Fiks, MD, Named Director of Clinical Futures

Alex Fiks, MD, MSCE, will lead the CHOP Research Institute on its continuous journey of discovery as director of Clincial Futures. A dedicated primary care pediatrician who maintains a robust research program aimed at improving the outcomes for ambulatory pediatric patients through practice-based research, Dr. Fiks is focused on improving health and health care decision-making through health information technology. Much of his research focuses on fostering shared decision-making between clinicians and families, often in the setting of behavioral health conditions. 

In a joint announcement about Dr. Fiks’ new role, Bryan Wolf, MD, PhD, chief scientific officer, and Richard Aplenc, MD, PhD, MSCE, chief clinical research officer, shared that one of his first contributions will be to help lead a strategic planning process for Clinical Futures. This planning process will address areas critical to the Clinical Futures' continued evolution and success such as leveraging advanced analytics, informatics, and general clinical effectiveness questions into patient care to enhance CHOP’s care delivery model.

In Dr. Fiks’ pursuit of ways the electronic health record data may be used to improve primary care, medication use, and child health, he has overseen the creation of the American Academy of Pediatrics Pediatric Research in Office Settings Network’s Collaborative Electronic Reporting for Comparative Effectiveness Research (CER2). This electronic health record database is designed to support pharmacoepidemiologic and other comparative effectiveness studies, and includes more than 2 million U.S. children from multiple health systems.

In addition to his research program and new director role, Dr. Fiks is medical director for the Pediatric Research Consortium, CHOP's practice-based research network; a founding member of the Department of Biomedical and Health Informatics; and a PolicyLab faculty member. He serves as director of the Possibilities Project, is an associate professor of pediatrics, and holds a Distinguished Endowed Chair in the Department of Pediatrics at the University of Pennsylvania and CHOP.


Catch up on the headlines from our last edition of In the News:

  • Dr. Gmuca Receives Rheumatology Research Foundation Award
  • South Jersey Summer Institute for Educators Visits CHOP
  • PolicyLab Sheds Light on Rural Home Visiting Programs
  • Dr. Krishnaswamy Recognized by American Society of Hematology
  • Study on Underreported Child Abuse in Army Families

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