Refining Tools, Techniques to Transform Pediatric Medicine

A team of Children's Hospital of Philadelphia and University of Pennsylvania investigators developed a proof-of-concept model for delivering gene-editing tools to the bone marrow. The approach, described in the journal Science, could expand access and reduce the cost of gene therapies for blood disorders.

"Right now, if you want to treat hematologic diseases like sickle cell disease and beta thalassemia with gene therapy, patients must receive conditioning treatments like chemotherapy to make space for the new, corrected blood cells, which is both expensive and comes with risks," said co-senior author Stefano Rivella, PhD, the Kwame Ohene-Frempong Chair in Pediatric Hematology at CHOP.

The researchers showed that it is possible to replace diseased blood cells with corrected ones directly within the body, eliminating the need for myeloablative conditioning treatments and streamlining the delivery of these potentially life-changing treatments.

"The potential of this technology is transformative," Dr. Rivella said. "In this paper, the technology is meant for bone marrow and red blood cell diseases. But this technology can potentially treat other diseases. If we could deliver a cargo that corrects a mutation in the bone marrow, we can conceive alternative formulations to correct mutation in the brain, lung, or liver — this is the technology that will allow us to do that."

In a development that could accelerate the discovery of new diagnostics and treatments for a wide range of diseases, researchers from Children's Hospital of Philadelphia developed a technology for targeted sequencing of full-length RNA molecules. The technology, called TEQUILA-seq, is cost-effective compared with other available methods for RNA sequencing and can be used for a variety of research and clinical purposes.

RNA sequencing is used to study how changes in RNA molecules can lead to diseases such as cancer. Current "long read" RNA sequencing platforms evaluate molecules that are more than 10,000 bases in length, but they are only modestly effective. Targeted sequencing, which involves enriching specific nucleic acid sequences before sequencing, is a way to overcome this, but can be expensive and complex to do.

"TEQUILA-seq solves that problem by being both inexpensive and easy to use," said Lan Lin, PhD, assistant professor of Pathology and Laboratory Medicine and a principle investigator in the Raymond G. Perelman Center for Cellular and Molecular Therapeutics. "The technology can be adapted by users for different purposes, and researchers can choose which genes they want to sequence and make the reagents for target capture in their own labs. This has the potential to accelerate discovery of new diagnostic and therapeutic solutions for a wide range of diseases."

Using data from more than 1,000 newborns, researchers from the Neuroscience Center at Children's Hospital of Philadelphia have developed a prediction model that determines which newborn babies are likely to experience seizures in the Neonatal Intensive Care Unit (NICU).

This model could be incorporated into routine care to help the clinical team decide which babies will need electroencephalograms (EEGs) and which babies can be safely managed in the NICU without monitoring through EEGs.

"This data helped us optimize which newborns should receive EEG monitoring in the NICU," said first study author Jillian McKee, MD, PhD, a neurogeneticists and epileptologists provider with the Epilepsy Neurogenetics Initiative (ENGIN) Frontier Program at CHOP.

The researchers built their seizure prediction models based on standardized EEG features reported in electronic medical records. The retrospective study found that these models could predict seizures, and particularly seizures in newborns with temporary lack of oxygen to the brain, known as hypoxic-ischemic encephalopathy (HIE), with more than 90% accuracy. The models could be tuned to not miss seizures, performing with sensitivity of up to 97% in the overall cohort and 100% among newborns with HIE while maintaining high precision.

"If we can further validate this model, it could enable a more targeted use of limited EEG resources by reducing EEG use in low-risk patients, which will make care of babies with neurological concerns in the NICU more personalized and focused," said Ingo Helbig, MD, a pediatric neurologist in the Division of Neurology and co-director of ENGIN Frontier Program at CHOP. "We believe incorporating this model into real-time clinical practice could greatly improve the quality and efficiency of the care we deliver in these critical early days of life."

Children's Hospital of Philadelphia researchers showed that exposing the skin to a small amount of peanuts desensitized a majority of peanut-allergic toddlers, in a Phase III clinical trial.

Approximately 2% of children in the United States, Canada, and other western countries experience peanut allergies. Peanut oral immunotherapy (OIT) can desensitize allergic children to peanuts by having them consume very small but increasing amounts of the allergen over time. However, OIT involves regular, demanding dosing schedules, side effects, as well as the risk of allergic reactions.

As an alternative, researchers have been investigating the use of epicutaneous immunotherapy (EPIT), which involves a patch containing a small amount of allergen that is placed on a child's back, exposing the immune system to a very low level of allergen with less risk of a systemic reaction.

After a year of treatment in this trial, a significantly larger percentage of those wearing the peanut patch were able to tolerate the required peanut dose – 67% of those wearing the interventional patch versus 33.5% of those wearing the placebo patch.

"Although an allergy patch won't necessarily work for all toddlers, this study shows that it could be one more tool in an allergist's toolbox to help prevent a life-threatening allergic reaction," said Terri Brown-Whitehorn, MD, an attending physician in the Division of Allergy and Immunology and co-leader of the Food Allergy Center Frontier Program. "If we can find ways to reprogram these children's immune systems, that's a step in the right direction."

Researchers from Children's Hospital of Philadelphia and Drexel University created an algorithm to analyze 53 million patient notes from more than 1.5 million individual patients to identify similarities in their medical histories that can help pinpoint potential risks for developing future diseases and the trajectory of those conditions.

This method of identifying phenotypic similarities exceeds the capacity of any other current computational models. The technique demonstrated a high degree of agreement with the judgment of experts in the various clinical fields represented in this data.

By analyzing data from 1,504,582 patients with a variety of diagnoses and syndromes with 53,955,360 electronic notes in the Arcus data repository, the researchers identified 9,477 distinct phenotypes. Arcus is a suite of tools and services developed at CHOP that links biological, clinical, research, and environmental data for the purpose of conducting innovative, data-driven research.

"The algorithm we developed in this study has the potential to be utilized in finding similarities between clinical trajectories and identifying novel genetic causes of diseases," said Ingo Helbig, MD, a pediatric neurologist in CHOP's Epilepsy Neurogenetics Initiative (ENGIN) Frontier Program and scientific director of the Arcus Omics program. "This will allow us to use machine learning in tandem with existing methods to analyze risks and patient prognoses in a more efficient manner at large scale."