Innovation at the Forefront of Genomic Medicine
Post Date: May 2, 2025 | Publish Date:
Genetic and Genomic Contributors to Health and Disease
Research Annual Report 2024
Investments grow in our mission to study, diagnose and treat a wide range of rare and not-so-rare conditions linked to genetic variations.
In the rapidly evolving world of genomic research, investigators at Cincinnati Children’s leverage the latest technology to conduct a wide range of basic, translational and clinical studies. Here, investigators conduct leading-edge data analysis and develop cell and animal models that accelerate discovery.
We are proud to be a National Organization for Rare Disorders (NORD) Rare Disease Center of Excellence, where we collaborate with a large network of investigators and caregivers to expand access, advance care, and promote research for people with rare diseases. Key programs based at Cincinnati Children’s include
the Center for Circadian Medicine, the Center for Pediatric Genomics, and the Discover Together Biobank. Research highlights from fiscal 2024 include:
Launching the Applied Gene and Cell Therapy Center
Cincinnati Children’s is investing $60 million to create an Applied Gene and Cell Therapy Center in Sharonville, OH. The facility will occupy a 111,000-square-foot building and will focus on producing gene and cell therapy products that meet Current Good Manufacturing Practice (cGMP) standards.
The new center will enable more clinical trials of innovative drugs and biological therapeutics for patients with cancer, blood diseases, or genetic disorders. The project builds on the success of our Translational Core Laboratory, which has been a leader in early-phase clinical trials for over 15 years.
“We are deeply invested in pediatric research that focuses on gene and cell therapy, which benefits children and families in our region and around the world,” says Steve Davis, MD, MMM, president and CEO of Cincinnati Children’s. “The Applied Gene and Cell Therapy Center will expand on the research efforts that have already earned our health system recognition by Fortune as one of America’s Most Innovative Companies, and which also contributed to U.S. News & World Report ranking Cincinnati Children’s as No. 1 in the nation for pediatric cancer care.”
The renovation is expected to be completed by summer 2025, and the facility will ultimately house about 100 employees, including biologists and other specialists focused on quality assurance, regulatory compliance and plant operations.
GEMINI Study Demonstrates Value of Whole Genome Sequencing for Diagnosing Genetic Disorders
The complex effort to accurately resolve medical mysteries involving newborns and infants with rare genetic disorders has generated a fleet of quick, moderate-cost, but narrowly focused genetic testing tools. Turns out, many such tests are too narrowly focused.
Jae Kim, MD, PhD, co-director of the Perinatal Institute and division director of Neonatology at Cincinnati Children’s, was a co-author of a multicenter study published in JAMA reporting that a common “rapid” genetic test misses more diagnoses associated with rare disorders than whole genome sequencing (WGS).
After studying data from more than 400 newborns and infants, the researchers found that whole genome testing (that identifies variants among all 20,000 genes in the human body) found known genetic disorders in 49% of the patients. But a narrower test that looks at just 1,700 gene variants detected disorders in only 27% of the cases.
The study was led by researchers at Tufts and Brown universities, but Cincinnati Children’s provided the most study participants.
“Whole genome sequencing has rapidly emerged as the standard of care for newborn genetic testing, and this paper is helping to accelerate this change,” Kim says.
Teams using WGS are making earlier diagnoses of factor XIII deficiency, retinoblastoma, malignant hyperthermia and other conditions. In one case, a care team using WGS testing helped diagnose Kabuki syndrome within the first two weeks after the child was born, when the average time to an accurate diagnosis is about five years.
A New Chapter in Early-Stage Development: The COG Model
The Clock-Dependent Oscillatory Gradient (COG) model, developed by a team led by Ertugrul Ozbudak, PhD, and Cassandra McDaniel, offers a new perspective on somite segmentation, a critical process in early skeletal and muscle development.
The COG model emerged from studies on the dynamics of a segmentation clock driven by MAPK signaling in zebrafish embryos. The team’s findings, published in Science Advances, demonstrate that human intervention can rescue somite segmentation in the absence of a natural molecular clock.
Co-authors say this breakthrough has significant implications for tissue engineering, stem cell research and organoid development, potentially leading to new therapies for developmental disorders.
New Molecular Map of a Rare Disease Demonstrates Power of ‘Massively Parallel Reporter Assays’
Research led by Leah Kottyan, PhD, and Matthew Weirauch, PhD, may improve how genetic risk can be incorporated into decision making when clinicians seek to provide personalized therapies for children with rare diseases.
Their findings, published in the American Journal of Human Genetics, involved using a novel, DNA-based tool called massively parallel reporter assays (MPRA) to generate a comprehensive molecular map of eosinophilic esophagitis (EoE), a rare and severe form of food allergy. The map highlights 32 genetic variants that change gene expression levels in people with the condition.
After identifying the functions of the 32 risk variants, Kottyan and Weirauch went on to identify transcription factors that mediate the genetic risk of EoE. These transcription factors include GATA3, a key regulator of allergic inflammation, and USF1, which is overexpressed in biopsies of patients with EoE. Now validated, these transcription factors and their gene targets may become candidates for future diagnostic and therapeutic tools.
TSLP Inhibitors Emerge as Potential Therapy for Eosinophilic Esophagitis
In another study exploring eosinophilic esophagitis, a study published in Science Signaling details how the cytokine TSLP enhances allergic inflammatory response in human immune cells—suggesting that a blood test can be developed to identify a subset of people with eosinophilic esophagitis (EoE) who may benefit from high-cost monoclonal antibody treatments.
Unlike studies based heavily on mouse models, first author Yrina Rochman, PhD, corresponding author Marc Rothenberg, MD, PhD, and colleagues showed how TSLP modified the expression of 212 genes in human tissue samples. They found that TSLP directly affects human memory CD4+ T cells in a “feed-forward loop” that resulted in a cascade of reactions, all of which contribute to allergic inflammation.
“In light of these results and the high clinical cost of anti-TSLP biologics, our study expands the rationale for a noninvasive screening test before treatment, aiming to offer anti-TSLP treatment especially to patients with memory CD4+ T cells that exhibit high responsiveness to TSLP,” Rothenberg says.
Center for Pediatric Genomics Funds 8 Pilot Projects
Since 2014, the Center for Pediatric Genomics has invested $1 million annually to fund internal pilot projects that engage both clinical and bench researchers in advancing discovery and translation in genomics. In 2024, the center funded these projects:
- Epigenetic Mechanisms of Disrupted Neurodevelopment in Kabuki Syndrome Type 1: This project seeks to identify molecular targets for potential therapies by using an induced pluripotent cell system to understand the neurodifferentiation defects associated with KMT2D haploinsufficiency.
- Role of MRP9/ABCC12 in Biliary Homeostasis and Fibrosis: This project investigates the role of MRP9, encoded by ABCC12, in cholangiocyte health and its potential as a risk factor in biliary fibrosis.
- A Novel Gene Therapy Strategy for GNAQ-mediated Vascular Anomalies: This project aims to develop a targeted gene therapy using a genetic mouse model and adeno-associated viruses (AAVs) to treat GNAQ-driven vascular tumors.
- Immunologic and Inflammatory Responses to Mechanical Circulation Device Exposure Using Single Cell Genomic Expression Analyses: This project explores the role of factor XII in these complications, aiming to develop new therapies to prevent dangerous clotting and immune sequelae associated with these devices.
- Antibody Gene Biomarkers of Food Allergy: This project aims to develop novel diagnostic biomarkers by investigating the cell types responsible for inappropriate food reactivity.
- Investigating Systemic Regulation of Mineralization by Human Disease Gene SOX10: This project investigates a new symptom found in a SOX10 animal model: deficient bone mineralization linked to disrupted systemic mineral regulation.
- Systematic Functional Characterization of PRDM1 and Pioneer Factors by LentiMPRA: This project aims to understand the gene regulatory principles of pioneer transcription factors (TFs) and repressors in order to enhance precise manipulations of cell fate in regenerative medicine.
- High Throughput NGS-Based Assays to Predict ATM Missense VUS Pathogenicity in A-T: This project focuses on ataxia-telangiectasia (A-T), aiming to establish a high throughput system for interpreting the clinical impact of ATM variants of uncertain significance (VUS) in order to benefit A-T patients and their families.
Learn more about our latest genomics research
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About this blog
The Research Horizons blog features news and insights about the latest discoveries and innovations developed by the scientists of Cincinnati Children's. This blog does not provide medical advice, diagnosis, or treatment.
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