Advancing pediatric genetic medicine through interdisciplinary collaboration

The Center for Genetic Medicine Research (CGMR) at Children’s National Hospital continued to serve as a hub for groundbreaking discoveries through its multidisciplinary approach to pediatric genetic research during the last academic year. By fostering collaboration among experts from diverse fields, the CGMR addresses some of the most complex and rare genetic disorders, utilizing genomics and advanced bioinformatics to uncover the molecular mechanisms behind these conditions. This cross-disciplinary environment enables the development of novel therapies for a wide range of diseases affecting children.

One of the CGMR’s most promising areas of research focuses on the gene SPIN4 and its role in skeletal growth. Led by pediatric endocrinologist Youn Hee Jee, M.D., this project benefits from the expertise of Wei Li, Ph.D., a specialist in genome editing. Together, they are using CRISPR-Cas9 technologies to produce knockout cell lines and explore how SPIN4 impacts skeletal development during childhood and puberty. In parallel, Dr. Jee is working with Yi-Wen Chen, Ph.D., M.S., D.V.M., to investigate the epigenetic mechanisms that regulate SPIN4 and skeletal muscle remodeling, leveraging Dr. Chen’s expertise in long-range sequencing and nucleic acid modifications. These efforts are aimed at developing therapeutic interventions for growth and muscle disorders​.

In another innovative project, Dr. Jee collaborated with a team of specialists, including Tayyba Riaz Anwar, M.D., Marius George Linguraru, D.Phil., M.A., M.Sc., Hiroki Morizono, Ph.D., and Andrew Dauber, M.D., M.M.Sc., to combine machine learning, biomedical informatics and bone health research. This multidisciplinary team is investigating the genetic basis of bone age by integrating predictive analytics with clinical data, leading to improved diagnostic tools for growth-related conditions​.

The CGMR is also at the forefront of bioinformatics research. Susan Knoblach, Ph.D., Christopher Lazarski, Ph.D., and Dr. Morizono are spearheading a project to apply bioinformatics and machine learning tools to uncover predictive biomarkers in pediatric clinical trial samples. The team is using spectral flow cytometry to analyze immune blood cells in cancer patients undergoing T-cell therapies. Their research seeks to identify patterns of immune response, potentially improving the efficacy of adoptive cellular immunotherapy.

Within the realm of rare growth disorders, Dr. Jee, along with Arthur Ko, Ph.D., and Seth Berger, M.D., Ph.D., is focusing on discovering novel pathogenic variants in human growth disorders. Dr. Ko, a data scientist, and Dr. Berger, a medical geneticist specializing in bioinformatics, are screening intronic regions for splicing enhancers and pathogenic variants. This research is essential for understanding the genetic mechanisms underlying growth disorders and has the potential to lead to new therapeutic targets​.

The CGMR is making significant strides in muscular dystrophy research as well. Jyoti K. Jaiswal, M.Sc., Ph.D., and James Novak, Ph.D., are collaborating on several projects aimed at treating Duchenne Muscular Dystrophy (DMD). Their work on pro-resolution therapies seeks to reduce cardiac and skeletal muscle injury, a major concern in DMD. Dr. Novak, who specializes in mouse models of DMD, and Dr. Jaiswal, an expert in cell biology and inflammation, are combining their expertise to explore new therapeutic strategies. Additionally, they are working together on an oligonucleotide therapy designed to enhance dystrophin restorative treatment, furthering efforts to slow the progression of DMD.

The Center’s collaborative efforts extend beyond muscle disorders. Dr. Jaiswal and Gustavo Nino, M.D., M.S.H.S., D’ABSM, are investigating the molecular mechanisms of airway antiviral responses in children with Trisomy 21. Their research explores how children with Down syndrome respond to viral infections, including SARS-CoV-2. By combining clinical virology with cell biology, this project could lead to better treatments for respiratory infections in vulnerable pediatric populations.

In other areas, Ioannis Koutroulis, M.D., Ph.D., M.B.A., and Panagiotis Kratimenos, M.D., Ph.D., are collaborating on research related to sepsis metabolism and the immune response to cerebellar injury. Dr. Koutroulis’ expertise in emergency medicine and metabolism complements Dr. Kratimenos’ focus on neurodevelopmental research, providing a comprehensive approach to understanding how energy production influences immune responses in brain injury.

Benjamin Liu, Ph.D., and Dr. Chen are working on developing novel diagnostic tools for detecting central nervous system (CNS) infections in children. Dr. Chen’s proficiency in long-read sequencing technologies, particularly Oxford Nanopore sequencing, is critical in advancing this project, which seeks to improve the speed and accuracy of CNS infection diagnoses.

Additionally, Youssef A. Kousa, M.S., D.O., Ph.D., Dr. Ko and Tarik Haydar, Ph.D., are leading research into the viral neurobiology of the prenatal brain. Their work focuses on understanding how enzymes and lysosomes affect brain injury during prenatal development. This project aims to uncover genetic risk factors and therapeutic targets for brain injuries caused by viral infections during pregnancy. By exploring the enzymatic and lysosomal pathways that play a role in brain injury, the research led by Dr. Kousa, Dr. Ko and Dr. Haydar could pave the way for prenatal neuro-precision interventions that protect the developing brain from damage.

Throughout these diverse research initiatives, the CGMR has cultivated a collaborative atmosphere that brings together junior and senior investigators from multiple disciplines. This collaborative model allows for the blending of complementary areas of expertise, pushing the boundaries of pediatric genetic research. By combining state-of-the-art techniques in genomics, bioinformatics and molecular biology with clinical insights, the CGMR is making significant strides in understanding the genetic basis of diseases and developing targeted treatments that improve the lives of children affected by rare and complex genetic conditions.

The Center’s ongoing work in areas such as skeletal growth disorders, muscular dystrophy, bioinformatics, CNS infections and prenatal brain injury highlights the importance of interdisciplinary research in advancing medical knowledge and therapeutic development. Through its collaborative efforts, the CGMR remains at the forefront of pediatric genetic research, ensuring that new discoveries continue to translate into tangible benefits for children around the world.