Bringing Our Science to the Bedside

Researchers from Children’s Hospital of Philadelphia and the University of Pennsylvania Scheie Eye Institute improved vision in two children with a severe inherited form of retinal blindness called Leber Congenital Amaurosis, who participated in an early phase, multi-institutional clinical trial.

By using CRISPR/Cas9 gene editing — the Nobel Prize-winning technology that cuts and modifies DNA with pinpoint accuracy — the team showed that the experimental gene-editing treatment (EDIT-101, Editas Medicine and Allergan) was safe and improved sight in half of the patients who received it. The New England Journal of Medicine published the findings.

Tomas Aleman, MD

"Our patients are the first congenitally blind children to be treated with gene-editing, which significantly improved their daytime vision," said Tomas Aleman, MD, CHOP pediatric ophthalmologist, who served as a site principal investigator and study co-author. "Our hope is that the study will pave the road for treatments of younger children with similar conditions and further improvements in vision."

Children's Hospital of Philadelphia surgeons performed the first gene therapy procedure for hereditary hearing loss, in October 2023. This milestone represents an important step in possible treatment options for patients around the globe with hearing loss caused by genetic mutations, as well as marking another scientific advance for gene and cell therapy.

In a minimally invasive surgical procedure, John Germiller, MD, PhD, an attending surgeon and Director of Clinical Research in the Division of Otolaryngology, placed a single, small dose of functioning otoferlin (OTOF) genes encased in a viral vector — a modified form of a non-disease-causing virus — into cells of the cochlea in an 11-year-old's inner ear.

Without functional otoferlin protein, sounds cannot be communicated from the ear to the brain, resulting in hearing loss. But with normal OTOF genes, the sensory cells function correctly so they can respond to sound and activate the auditory nerve to send impulses to the brain.

"As more patients at different ages are treated with this gene therapy, researchers will learn more about the degree to which hearing is improved and whether that level of hearing can be sustained over several years," Dr. Germiller said. "What we learn from following this first patient’s progress will help direct our efforts toward helping as many patients as we can." CHOP is one of four clinical trial sites in the world participating in this Phase 1/Phase 2 clinical research trial.

The Food and Drug Administration's approval of two gene therapies — exa-cel (Casgevy®, Vertex and CRISPR Therapeutics) and lovo-cel (Lyfgenia®, bluebird bio) — for sickle cell disease marks a turning point for an underserved patient population.

Exa-cel is the first-ever treatment to use the Nobel Prize-winning technology called CRISPR to edit a patient's DNA as a potential cure for disease. Lovo-cel introduces a new gene through a modified virus vector for a form of hemoglobin that is resistant to sickling.

Children's Hospital of Philadelphia, which served as a clinical trial site for both therapies, is an approved site to offer the new therapies.

"When we think about an option that is curative, it really has two important considerations," said Alexis Thompson, MD, MPH, Chief of the Division of Hematology at CHOP. "One is the possibility that the individual will be freed of the burden of this disease. The other is the hope that these individuals no longer require the degree of care and the expenses related to that care, and instead can look forward to having more full lifespans where they finish their educations, have jobs, raise families, and live the lives that they want."

Children's Hospital of Philadelphia researchers, as part of an international team, published the results of a key clinical trial that helped to inform the Food and Drug Administration approval of the monoclonal antibody dupilumab for the treatment of eosinophilic esophagitis (EoE) in pediatric patients between 1 and 11 years old.

Their findings appeared in the New England Journal of Medicine and built upon previous work that examined the safety and efficacy of dupilumab for adolescents and young adults with EoE.

"This manuscript and the related FDA approval finally provides a treatment option for our patients,” said study co-author Jonathan Spergel, MD, PhD, Co-leader of the Food Allergy Center and Section Chief of the Allergy Program at CHOP. "We are excited for our patients and new potential benefits for them."

EoE is a chronic allergic inflammatory disease of the esophagus that causes symptoms such as redness, swelling, and itchiness during an allergic reaction. Traditional treatments such as food elimination diets, topical glucocorticoids, proton-pump inhibitors, and esophageal dilation do not provide relief for approximately one-third of patients with EoE, and some experience negative side effects.

Results from this study revealed that histologic remission — meaning no inflammation was present — occurred in 68% of patients who received higher-exposure dupilumab and 58% of patients receiving lower-exposure dupilumab.

The Food and Drug Administration approved the one-time gene therapy fidanacogene elaparvovec (Beqvez®, Pfizer) for the treatment of adults with hemophilia B. The therapy has the potential to be life-changing for patients over 18 years old who have relied their entire lives on daily therapeutic injections.

For Katherine High, MD, a pioneer in the field of gene therapy and former CHOP scientist, and Lindsey George, MD, who led the Phase I/II clinical trial for the treatment, the FDA approval represents CHOP's role in basic and clinical research that helps bring life-saving gene therapies from the bench to the bedside.

"Dr. High and many at CHOP were fundamental in establishing that first set of rules — the regulatory playbook for gene therapy clinical trials — and those rules, for the most part, remain in place today," said Dr. George, an attending hematologist and Director of CHOP's Clinical In Vivo Gene Therapy group. "Years ago, hospital leadership said, 'Gene therapy has tremendous potential to impact pediatric health,' and they stayed true to that vision."

The Food and Drug Administration approved the use of palovarotene (Sohonos™, Ipsen), a retinoid agonist oral drug based on foundational research by the Pacifici Laboratory at Children's Hospital of Philadelphia. Palovarotene is the first treatment for heterotopic ossification (HO) in adults and children with fibrodysplasia ossificans progressiva (FOP), a debilitating, ultra-rare, and often fatal disease. It is approved for females who are 8-years-old and older, and for males who are 10-years-old and older.

"The dream of every biomedical researcher is to go from the lab to the bedside and discover a treatment that improves the lives of patients," said Maurizio Pacifici, PhD, Director of Research in the Orthopedic Center. "We are very excited that the FDA has approved this drug, as the patients currently lack an effective treatment that will slow down or block their debilitating disease."

HO is the formation of excess skeletal tissue at abnormal anatomical locations — outside the skeleton — and is caused by a genetic mutation in patients with FOP. Starting at the age of 2 or 3 in these children, HO begins through the upper body and then develops down the torso and along the limbs, forming either spontaneously or after local inflammation. Once the bone forms, it is irreversible and leads to loss of mobility, severe health complications and shortened life expectancy.

Dr. Pacifici has been studying the retinoic pathway to regulate cartilage and bone formation for more than 20 years. The drug he and colleagues developed is designed to mediate the interactions between the receptors, growth factors, and proteins within the retinoid signaling pathway to reduce new abnormal bone formation.

The Center for Violence Prevention (CVP) at Children's Hospital of Philadelphia celebrated 10 years of programming and research designed to reduce the impact and incidence of violence in surrounding communities. Established in 2013 following the mass shooting at Sandy Hook Elementary School, CHOP developed a comprehensive initiative that could not only be influential locally, but also serve over time as a national model for hospital-led violence prevention programming, training, and research.

Led by Co-directors Joel Fein, MD, MPH, and Stephen Leff, PhD, the multidisciplinary faculty and staff conduct research, help shape policy, engage community partners, and create, implement, and refine evidence-based interventions. CVP applies a trauma-informed, anti-racist lens to community programs and activities, promoting community resilience and supporting diversity of staff and faculty.

The Center's expansion and refinement of programs over the years is based on information that is gathered from CHOP and community stakeholders. CVP's current pillars are Aggression and Bullying Prevention, Community Violence and Trauma Support, Intimate Partner Violence Prevention, Suicide Prevention, Gun Safety, and Professional Development and Training.

"While we are proud of what we have been able to accomplish over our first 10 years, we also realize that our work is far from complete," noted Drs. Fein and Leff. "No child should ever experience trauma or violence, but if they do, they should not have to heal and recover alone. We hope to be here for them, creating new pathways for healing through our research — now and into the future."