Hartwell Awards Fund ‘Innovative, Early-Stage’ Research for Two CHOP Investigators

Two CHOP researchers are recipients of a 2021 Individual Biomedical Research Award from The Hartwell Foundation .

shafere1 [at] chop.edu (By Emily Shafer)

What is the relationship between histones, a class of proteins in the body, and a new group of pediatric genetic syndromes? Could there be a blood test in the future to identify foods that cause eosinophilic esophagitis (EoE), an allergic condition? These are research questions that Elizabeth Bhoj, MD, PhD, and David Hill, MD, PhD, will be tackling with research funding from the Hartwell Foundation.

Dr. Bhoj, attending physician in the Division of Human Genetics, and Dr. Hill, attending physician in the Division of Allergy and Immunology, are two of only 10 recipients nationally of a 2021 Hartwell Foundation Individual Biomedical Research Award. The Hartwell Foundation provides funding for innovative, early-stage biomedical research with the potential to benefit children in the United States. Hartwell Investigators receive support for three years at $100,000 direct cost per year.

Super Fundamental Class of Proteins

Elizabeth Bhoj, MD, PhD

A few years ago, Dr. Bhoj and her team found mutations in histones that opened doors to learning how these vital proteins are involved in neurodevelopment and neurodegeneration.

“We are going to be looking at a group of new pediatric genetic syndromes that are caused by mutations in these histones,” Dr. Bhoj said. “Histones are really important for controlling the packaging of DNA, but they are also really important for controlling when genes are turned on and off when cells divide. They are a super fundamental class of proteins.”

The title of Dr. Bhoj’s Hartwell-funded project is “Epigenetic Diagnosis and Targeted Treatment for Improving Cognitive Outcomes in Neurodevelopmental Disorders.” Such disabilities are associated with the function of the brain and nervous system and include, principally, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), as well as developmental delays and other forms of intellectual disability. Because the symptoms and behaviors of neurodevelopmental disorders may evolve as a child develops and many children have more than one condition, diagnosis may be difficult. Such disabilities are often complex in nature and origin and can create a significant burden to families.

Based upon her discovery that in children with neurodevelopmental disorders a novel, single histone gene mutation can be responsible for a specific neurodegeneration syndrome, Dr. Bhoj seeks to identify the genes that contribute to pediatric neurodevelopmental disorders. She hypothesizes that the activation and deactivation of genes in tightly controlled patterns are responsible for determining heritable epigenetic changes that can be specifically manipulated to improve childhood cognitive outcomes. If Dr. Bhoj is successful, development of a treatment for these syndromes will profoundly improve the quality of life of affected children and their families.

“I see patients 20% of my time, and those kids have either known or suspected genetic disorders,” Dr. Bhoj said. “I spend the other 80% of my time running a lab that helps those kids either get a diagnosis or get a treatment for their diagnosis. Those undiagnosed kids set the agenda for what we work on in the lab.”

Changing the Management of a Disease

David Hill, MD, PhD

EoE is a form of food allergy that is growing in prevalence. It is a chronic disease in which a type of white blood cell – eosinophils – builds up in the esophagus,

resulting in inflammation, tissue damage and scarring. Children with EoE experience chronic chest pain, reflux, and painful swallowing. Some children develop strictures that block food from passing from the mouth to the stomach. Unfortunately, there is no good clinical testing to identify the foods causing the disease; conventional allergy testing has not been helpful. There is no cure for EoE, and the only definitive therapy is removal of causal foods from the diet, a process that today requires repeated cycles of single food elimination followed by invasive endoscopy and biopsy. Dr. Hill is working to change this approach.

“It currently takes months or years to identify foods that are causing this disease in children, as they have to go through cycles of food elimination, followed by endoscopy and biopsy,” Dr. Hill said. “We’re developing a blood test that could potentially identify all the foods that are causing the disease, reducing the diagnostic time from years to weeks.”

The title of Dr. Hill’s Hartwell-funded project is “Food-Specific Memory T Cell Responses for Diagnosis and Monitoring of IgE-Independent Eosinophilic Esophagitis.” Based upon his discovery that children with EoE milk allergy have milk-activated memory T cells in their blood and the fact that this cell type is most indicative of persistence of an immunologic response, he hypothesizes that measurement of such food-specific T cells will inform EoE diagnosis and improve clinical care. He will seek to confirm in a prospective trial of 150 children if the presence of milk-activated memory T cells in the blood will predict clinical EoE milk allergy. If confirmed, the clinical translation of Dr. Hill’s approach will revolutionize the diagnosis and management of this severe food allergy.