In Landmark Study, CHOP-Penn Team Treats Newborn With Base-Editing Therapy

By Lauren Ingeno

Developing any gene therapy, particularly an in vivo therapy, takes intense time and resources, which is why most drug development efforts have focused on correcting highly recurrent variants in a few common genetic diseases. Meanwhile, children with rare diseases — which may be individually uncommon but collectively affect millions — are left with few therapeutic options.

KJ, who was diagnosed shortly after birth with a urea cycle disorder called CPS1 deficiency syndrome, is one of those patients. Urea cycle disorders are a group of inherited diseases that prevent the liver’s ability to remove toxic waste, called ammonia, from the bloodstream. When ammonia accumulates, it can reach the brain and cause severe damage.

In a historic medical breakthrough, a team at Children’s Hospital of Philadelphia and Penn Medicine successfully treated KJ with a CRISPR-based, gene-editing therapy, based on years of preclinical research.

“This is the first time that a patient has received a personalized gene-editing drug,” said Rebecca Ahrens-Nicklas, MD, PhD, Director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at CHOP and an Assistant Professor of Pediatrics the University of Pennsylvania’s Perelman School of Medicine.

After receiving three doses of his bespoke therapy without any safety concerns, KJ has tolerated increased protein in his diet and needed less nitrogen scavenger medication. More time is needed to fully evaluate the long-term effects of the treatment, so the team will continue to monitor KJ closely.

“When the doctors came to us with their idea, we put our trust in them, in the hopes that it could help not just KJ but other families in our position,” said KJ’s mother, Nicole.

Published in The New England Journal of Medicine and presented at the American Society of Gene & Cell Therapy Annual Meeting, the landmark case paves the way for clinicians to personalize the gene-editing technology for other individual patients with genetic diseases caused by ultra-rare “N-of-1” variants.

“As a metabolic and rare disease pediatrician, I have so many patients with huge, unmet needs,” said Dr. Ahrens-Nicklas, who is a co-corresponding author on the NEJM paper, alongside Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research at Penn Medicine and a Professor of Pediatrics at CHOP. “I hope that this study can open the door to potential therapies for more patients.”

New Types of CRISPR-based Technology

CRISPR is a Nobel Prize-winning gene-editing technology that chemically cuts and modifies a patient’s genetic code. The technique has revolutionized treatment for a handful of diseases, including sickle cell disease and beta-thalassemia.

However, relatively few medical conditions lend themselves to a “one-size-fits-all” corrective gene editing approach, where a single therapy treats all affected individuals. For most genetic diseases, especially ultra-rare ones, patients have many disease-causing variants in one or more genes.

Two new types of CRISPR-based technology — base editing and prime editing — can rewrite individual DNA letters, or bases, in the genome without making double-stranded DNA breaks. These methods are both more flexible and more precise than conventional CRISPR/Cas9 and have the potential to address over 90% of disease-causing genetic variants, according to Dr. Ahrens-Nicklas.

Urea cycle disorders originate from many gene variants, and symptoms often appear days after birth. While liver transplant is one treatment option, it is often not immediately available for patients like KJ who are too small to undergo the procedure.

To fill this treatment gap, Dr. Ahrens-Nicklas teamed up with Dr. Musunuru in 2023 to study the feasibility of creating customized gene-editing therapies for individual patients, building upon many years of research into rare metabolic disorders, as well as the feasibility of gene editing to treat patients.

With funding from the National Institutes of Health, the researchers sought to create a scientific platform and regulatory framework for the rapid development of personalized therapies for individual patients with rare genetic diseases.

They focused their initial efforts on urea cycle disorders. When KJ was diagnosed with a CPS1 variant, the team approached his parents about working to develop an experimental, CRISPR-based therapy for their son.

The researchers designed and manufactured a base-editing therapy made specifically for KJ. The medicine would be delivered via lipid nanoparticles to the liver to correct KJ’s faulty enzyme. The team also performed a patient-specific off-target analysis to ensure that the treatment would not lead to unintended changes to the genome.

Collaborating to Achieve Personalized Therapies

During this time, Dr. Ahrens-Nicklas and Dr. Musunuru consulted a wide range of medical experts across CHOP departments and divisions, including Liver Transplant, Immunology, Medical Ethics, and Clinical In Vivo Gene Therapy.

Between six and seven months after birth, KJ received his first dose of the customized gene therapy.

“I realized the immense responsibility of what we were undertaking,” Dr. Ahrens-Nicklas said. “I was also incredibly grateful for the family putting their trust in us.”

In the weeks following, doctors performed various exams, testing KJ’s ammonia and glutamine levels while adjusting his diet and medications.

“Every day, we're trying to adjust how we're managing and caring for KJ and seeing if he can tolerate a little bit more of a typical diet and lower doses of his medications,” Dr. Ahrens-Nicklas said.

The CHOP-Penn research team said KJ has experienced no serious adverse side effects from the treatment to date. While it remains to be seen whether KJ’s disease has been fully resolved and whether the correction will be durable, his parents say he is growing and developing as a healthy child would.

“We hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life,” Dr. Musunuru said. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”

This study was supported by grants from the National Institutes of Health Somatic Cell Genome Editing Program (U01TR005355, U19NS132301), as well as additional NIH grants (R35HL145203, U19NS132303, DP2CA281401, P01HL142494). In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation. Additional funding was provided by the CHOP Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program.

For more information, see the CHOP press release and watch KJ’s video story.