Researchers at Children’s Hospital of Philadelphia are using genetic and clinical data for breakthroughs in rare paediatric diseases.Credit: Yuichiro Chino/Getty
“When these children and their families visit your lab and learn what you're doing for patients like them, there’s a light that comes on in their eyes,” explains Beverly Davidson who, among her many responsibilities at Children’s Hospital of Philadelphia (CHOP), serves as the chief scientific strategy officer (CSSO) and the director of the Raymond G Perelman Center for Cellular and Molecular Therapeutics (CCMT).
Such excitement fuels Davidson’s drive to improve paediatric healthcare. In her laboratory, she focuses on the development of cell and gene therapies and how they can become life-saving treatments for childhood neurodegenerative diseases. As CSSO, she focuses on furthering the hospital’s long tradition of innovation.
Founded in 1855, CHOP became the first hospital in the United States solely dedicated to the diagnosis and treatment of sick children1. However, time and tradition have a way of relegating forerunners to the history books, if they lack the ability to evolve.
Not CHOP, however; the hospital has remained at the leading edge of paediatric healthcare, having had a pivotal role in many of the past century’s biggest medical breakthroughs: from the invention of the Isolette neonatal incubator in the 1930s2,3, through the identification of a potentially lethal inherited metabolic disorder in the 1980s4, to the administration of the first CAR T-cell therapy in a paediatric patient, in 20125.
“To keep making a difference,” Davidson adds, “we really need to keep thinking outside the box.”
An embrace of translational genomics
“I wrote a business plan to build a comprehensive genomics centre from ground up. In record time, the CHOP Board of Trustees agreed to it,” recalls Hakon Hakonarson. As the founding director of the Center for Applied Genomics (CAG) and CHOP’s endowed chair of genomic research, Hakonarson is deeply familiar with the hospital’s ability to embrace new technology for innovative therapies and new applications.
Hakonarson’s proposal was made in 2006 and came because of the ambitious project he was leading to establish a specialized genomics centre within CHOP, one whose primary focus would revolve around the use of genetic data as a guiding tool in the diagnosis and treatment of paediatric conditions.
“When I proposed CAG, it was designed to be a large-scale, comprehensive genetics programme,” Hakonarson explains. “We would handle every aspect, from patient recruitment, phenotyping, and sample collection, to wet and dry lab work — and the translation of those findings into clinical innovations.”
At the time, genome-wide genotyping (GWAS) and next-generation sequencing (NGS) were relatively new technologies with uncertain clinical value. To invest millions in building a comprehensive programme centred on such nascent technology was a considerable risk. “At the scale we were proposing,” says Hakonarson, “no-one would have taken this on, other than CHOP.”
The risk paid off. Since its opening, researchers from CAG have contributed to more than 1,000 publications, have supported the development of many new therapeutics and, in concrete ways, have helped save patient lives.
In 2019, CHOP admitted a 12-year-old boy who had developed a rare lymphatic vascular anomaly that increasingly restricted his breathing. Standard therapeutics failed to improve his condition, and survival seemed unlikely. However, collaboration among physicians and researchers in CAG provided a solution. “We discovered a causative gene mutation in two patients, identified an existing drug that acts on that gene’s pathway, showed that the drug relieves the condition in lab animal models, and then successfully treated the original patient,” explained Hakonarson in an interview at the time. Within months of initiating the off-label treatment, the child’s disease had receded.
The CAG team is still making similar breakthroughs. A 2023 study exploring lymphatic vascular anomalies led to a new medical therapy6. Studies like these demonstrate the value of genetic data in driving translational research at CHOP.
CHOP’s Epilepsy NeuroGenetics Initiative develops personalized care plans for children with rare genetic disorders, like Lexi, who was born with beta-propeller protein-associated neurodegeneration — a disorder caused by mutations in the gene WDR45.Credit: Children's Hospital of Philadelphia
The value of data integration, multi-omics, and de-siloing
“Genetic data in and of itself is only the first step,” says Ingo Helbig, a paediatric neurologist and director of genomic science at CHOP’s Epilepsy NeuroGenetics Initiative (ENGIN).
ENGIN is one of CHOP’s Frontier Programs, a group of initiatives that pioneer advances in translational paediatric care. “You need genetic data to be connected with clinical data, and after decades of amazing progress in the genomics field, that’s where the current bottleneck is.”
Like Hakonarson, Helbig’s research involves sifting through large datasets in search of patterns: clues that might explain a child’s symptoms and point to an effective therapy. As NGS technology has advanced, building large genetic datasets has become increasingly routine. However, bringing the varied descriptors of a patient’s symptoms together, and converting these data into a uniform format for analysis, is a growing challenge — confounded partly by data siloing, and partly because of differences in how providers and researchers describe symptoms. Collectively, this has a cascading effect on genomics research, particularly in the rare disease space where promising therapies are emerging, but real-world data are missing.
Helbig and his colleagues at CHOP are working to resolve this through the computational analysis of clinical data and electronic medical records. “When we look at rare diseases, one very typical misunderstanding is that we don't have enough clinical data,” he explains. However, a patient’s lifetime can unfold into a rich medical history in the electronic medical records. With appropriate analysis, these sources can help paint a comprehensive picture of a disease’s phenotypic profile. “It's not so much that the data are lacking, it's just that we don’t really understand them yet in their native format,” he explains.
In 2020, Helbig and his colleagues published a study7 examining nearly 32,000 clinical terms found in the files of 846 patients for whom DNA sequencing data was available. Through a computational framework that allows standardized language across clinical terms — thus enabling data pooling and analyses — the team was able to tease out genetic associations among the data. One such pattern identified a subset of patients who had mutations in the SCN1A gene and a telling constellation of symptoms that pointed to a form of genetic epilepsy known as Dravet Syndrome.
“None of these patients had been clinically diagnosed with Dravet Syndrome,” Helbig explains. “We could see the patterns that their care providers — who were separated in time and space — could not see when they entered the data.”
Helbig’s work adds to a broader effort at CHOP to leverage clinical data for multi-omics research. Generally, multi-omics describes large, hypothesis-free data sets that each describe different levels of molecular information, such as proteins or DNA sequence. Helbig is also directing a project known as Arcus Omics, which aims to harmonize and analyse CHOP’s clinical and multi-omics data and make it easily accessible for its researchers.
“Many institutions have internal silos that prevent researchers from meaningfully extracting insights from genomic repositories, clinics, and multi-omics data,” says Helbig. Some siloing is necessary to protect patient data, which Arcus Omics preserves by keeping data within CHOP’s firewall and adhering to privacy practices beyond the capacity of individual research teams. But within this firewall, Helbig’s team removed partitions that would otherwise prevent deeper interrogation of genomic and clinical information. “This allows us to look at the connected data in a way that is simply not possible with external databases while maintaining privacy,” he explains.
While a powerful method, Helbig emphasizes that his work is only one step in the translational research pipeline. “Our team approaches the challenges of rare paediatric disorders by using data science to understand the complex clinical presentations, and how we connect a gene and the patient’s phenotype. Then Bev Davidson can come in with the gene therapy.”
A vector for change
“CHOP had the vision more than 15 years ago to make major investments in the cell and gene therapy space,” explains Davidson, whose work at CHOP has long focused on the development and integration of these advanced therapeutics in paediatric disease.
As the name suggests, these therapies target diseases using engineered cells or DNA/RNA. One of the most well-recognized is CAR T-cell therapy, where T cells are extracted, given a new chimeric antigen receptor (CAR) that targets a molecular marker uniquely expressed on the cancer cells, then readministered to fight disease.
Davidson’s researchers help develop and refine CAR T vectors and therapies, providing support in preclinical testing, proof of concept work, and beyond. Core services in CCMT provides CHOP investigators with clinical grade vehicles for these therapeutics, often viral vectors such as lenti- or adeno-associated viruses.
“CHOP has been a leader in manufacturing state-of-the-art vectors for almost two decades,” explains Davidson. CCMT Clinical Vector Core researchers provided vectors that led to the first FDA-approved CAR T-cell therapy, tisagenlecleucel (sold under the brand name Kymriah by Novartis). They also provided AAVs in trials that led to approved therapies for disorders such as inherited retinal disease and AADC, a rare neurotransmitter disorder.
“I’m very proud of the many clinical products we’ve provided and how the Cell and Gene Therapy Collaborative (CGTC) at CHOP continues to be pioneers in the field,” says Davidson. To facilitate this work, CHOP invests heavily in recruiting and supporting its scientists. “As an institution, we have the ability to treat and cure many seemingly intractable disorders thanks to the breadth and depth of expertise on our campus, as well as the support we provide through the CGTC.”
As with Helbig’s efforts to harmonize clinical and genomic data and Hakonarson’s deep genetic studies, Davidson’s work in the cell and gene therapy space highlights the innovative atmosphere that CHOP has cultivated since its beginning. “We're very forward thinking, because that's really necessary to move the needle and improve children's healthcare.”