Precision Medicine Shaping Next Generation of Breakthroughs



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Children's Hospital of Philadelphia aspires to be the global leader in pediatric and cell gene therapy discovery and treatment while continuing to shape the next generation of breakthroughs. 

The Cell and Gene Therapy Collaborative (CGTC) was established in 2020 to cultivate support for more CHOP-led research and to accelerate the pace of clinical development, in order to provide new therapies to children. The Collaborative will advance CHOP preclinical and clinical infrastructure in support of its vision.

Importantly, the CGTC will promote and foster continued collaboration and partnership across many areas of the Research Institute including the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, the Cellular Therapy and Transplant Section in the Division of Oncology, the Department of Pathology and Laboratory Medicine, the Division of Human Genetics, the Center for Applied Genomics, the Center for Fetal Research, and faculty members from research and clinical programs across the institution who contribute to this work.

Additionally, two CGTC grant programs support the development of promising cell and gene therapy programs from concept to clinical trial. Seed Grants promote early stage development of new ideas with the ultimate goal of preclinical proof of concept. Acceleration Grants support later-stage programs as they advance toward first-in-human testing.

The Roberts Individualized Medical Genetics Center (RIMGC) is a first-of-its-kind system to help families navigate the complex process of genetic and genomic testing and standardize how genetic testing is performed across different clinical disciplines. In a special report published in Pediatrics, RIMGC researchers, physicians, and counselors described the success of the model, their plans for the future, and important lessons learned. The team also provided a framework for making such a center work, as other hospital systems seek to replicate the model established at CHOP.

“We are deeply thankful to the Roberts family, whose generous support has pioneered the cutting-edge work we are doing in the RIMGC,” said Ian Krantz, MD, director of the RIMGC.

The report included five complex case studies of patients with medical conditions that were properly diagnosed thanks to the resources provided by RIMGC. One of them is the journey of Athan Fullam, who spent his first three months in the NICU receiving multiple, daily blood platelet transfusions, while his parents endured the uncertainty of tests that yielded no answers.

His diagnostic break came after Athan underwent whole exome sequencing and was found to have NLRC4-MAS, a novel, primary autoinflammatory syndrome caused by mutations in the NLRC4 gene. He is only the 21st patient to be identified with this rare, life-threatening condition. Athan began a clinical trial medication the next day, and his overall health took a positive turn.

The Cardiac Center is exploring the potential of virtual reality (VR) from the lab to the bedside. An innovative collaboration with diagnostic imaging experts enables cardiac clinicians to review echocardiograms, CTs, and MRIs in the 3D Imaging Review Suite using SlicerVR software. The results are 3D models that clinicians can resize, interact with, “hold” in their hand, and even step into. Surgeons can view heart anatomy from multiple angles and perspectives prior to surgery, preventing additional, unexpected procedures.

Clinician-researchers like Matthew Jolley, MD, cardiac anesthesiologist and SlicerVR developer, are leveraging VR capabilities to develop novel interventions and deliver individualized, precision care. Dr. Jolley received a grant to create tricuspid valve computer modeling methods and apply them to a large cohort of patients with hypoplastic left heart syndrome (HLHS). Characterized by incomplete development of the left heart, HLHS affects more than 1,000 live-born infants in the United States annually. This study will delineate the relationship between 3D tricuspid valve structure and valve dysfunction in HLHS, as well as design of patient-specific repairs informed by 3D structural analysis.

“Every kid is unique,” Dr. Jolley said. “Their images are unique. If you distill what we’re doing here, it’s image-based precision medicine.”

VR also enables more thorough medical education through a digitized registry that can be shared across institutions for the benefit of pediatric heart patients all over the world. Researchers in the Pediatric Heart Valve Center also hope to leverage VR in the development of a curated database that may one day inform valve repairs in patients with rare heart defects.

Ophir Shalem, PhD, of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, received a high-risk, high-reward grant to develop new functional genomics tools that use precise gene tagging to enable parallel measurements of gene expression dynamics for thousands of proteins, direct and rapid control of protein function, and a high-resolution study of protein unfolding that is associated with many human diseases. He was one of the pioneers in using the CRISPR system to develop genome-wide loss-of-function screens in mammalian cells.

The new approach will address some of the limitations of existing approaches used by scientists to identify and investigate candidate genes.

“This [research] is ‘high risk and high reward’ because it requires a significant amount of technological advances that currently do not exist — we need to develop a whole new set of tools,” said Dr. Shalem of his project, Direct and Rapid Control of Proteins at Scale. “Once everything is assembled together and successful, this novel screening method can be applied to a very, very wide range of possible questions.”

Noncoding regions that comprise the majority of the human genome involve structural variants that are large, complex genomic alterations that act as on/off gene-control switches. In cancer, which involves uncontrolled growth and division of cancer cells, noncoding mutations can play important roles as enhancers/promoters to oncogenes or tumor suppressor genes.

A CHOP-Penn study team developed a new computational algorithm called PANGEA (predictive analysis of noncoding genomic enhancer/promoter alterations) that helps scientists characterize a full spectrum of recurrent noncoding mutations. Researchers used the approach to identify and systematically prioritize 1,137 structural variants that may be causal noncoding mutations influencing the expression of more than 2,000 genes across five major types of pediatric cancers. Their analysis also revealed that coding and noncoding mutations affect distinct sets of genes and pathways, with little overlap.

“Because 95 percent of the genome is noncoding, presumably there will be a lot of driver noncoding mutations,” said Kai Tan, PhD, professor of Pediatrics, investigator with the Department of Biomedical and Health Informatics, and senior author of the study. “If we can understand noncoding mutations better, we can stratify patient subgroups and identify new subgroups. Even better, if you combine coding mutations and noncoding mutations, maybe we can find good targets for future research and therapy to move into clinical practice.”

PANGEA enables researchers to expand the types of pediatric cancer they can study, identify more noncoding mutations associated with these cancer types, and facilitate future experimental work to characterize and validate predictions about their oncogenic roles.