CHOP-Penn Team Fast-tracking Gene Therapies to Treat Rare Metabolic Diseases

By Lauren Ingeno

Researchers at Children’s Hospital of Philadelphia and the University of Pennsylvania are developing a platform to help fast-track personalized gene-editing therapies for patients with urea cycle disorders and other rare metabolic diseases.

The therapies will use a new, more flexible form of CRISPR technology called “prime editing” to correct each patient’s disease-causing gene variant directly and permanently.

“We’re creating a scientific platform and regulatory framework that will shorten the drug development timeline for patients who can’t wait 10 years for a new gene therapy to be tested and approved,” said Rebecca Ahrens-Nicklas, MD, PhD, an attending physician with the Metabolic Disease Program and the Division of Human Genetics at CHOP.

Dr. Ahrens-Nicklas is leading the project alongside Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine at Penn’s Perelman School of Medicine, with support from a $14 million grant from the National Institutes of Health.

Urea cycle disorders are a group of inherited genetic disorders that prevent the liver’s ability to remove toxic waste, called ammonia, from the bloodstream. Ammonia build-up can travel to the brain, causing severe damage.

Urea cycle disorders can be caused by many different gene variants, and infants can become sick within days of birth. A liver transplant is one treatment option, but infants are often too small to undergo the procedure, which can come with complications.

“During this wait, they have periods of elevated ammonia levels, which leads to ongoing neurologic consequences,” Dr. Ahrens-Nicklas said.

Despite previous attempts to treat rare metabolic diseases through gene therapy, success has been limited.

“Traditional gene therapies involve inserting a copy of a patient’s broken gene into the body,” Dr. Ahrens-Nicklas said. “But in the case of urea cycle disorders, the liver grows a huge amount between the neonatal period and adulthood. And as it grows, the corrected gene isn’t passed on to all its daughter cells because it doesn't integrate into the DNA.”

To overcome this challenge, Dr. Ahrens-Nicklas and the CHOP-Penn team are testing a new, more durable form of gene therapy called prime editing, which would allow liver cells to pass on their genetic “corrections” to new cells as they divide.

CRISPR-Cas9 is a therapeutic technique that scans the human genome for typos and uses “molecular scissors” to snip out and replace those errors with healthy DNA. In 2023, a gene therapy to treat sickle cell disease became the first-ever CRISPR treatment approved by the U.S. Food and Drug Administration for a human disease.

Prime editing is a newer, more flexible form of gene editing that works like CRISPR to perform targeted, small corrections to DNA. Unlike its counterpart, prime editing does not create double-stranded DNA breaks and does not require donor DNA templates.

“Prime editing is a theoretically safer option for patients that is under development for a variety of different clinical indications,” Dr. Ahrens-Nicklas said. “It's something that people are very excited about in terms of the potential to transform the way we treat genetic disease.”

After completing a series of studies in cells and animal models, the researchers aim to establish a therapeutic platform, comprising a single prime editor and adeno-associated viruses delivery system. The platform would have the ability to treat numerous metabolic diseases, also called inborn errors of metabolism. They also plan to design a master regulatory framework to move future therapies more seamlessly from the bench to the bedside.

At the end of the four-year grant, the researchers’ goal is to submit an investigational new drug application to launch a clinical trial at CHOP that will test the safety and efficacy of the prime editing therapy on patients with urea cycle disorders.

CHOP is uniquely positioned to lead the first in-human clinical trial for a prime-editing therapy to treat rare metabolic diseases, Dr. Ahrens-Nicklas said

“Not only do we have the expertise in urea cycle disorders and all of the other specialists required to support urea cycle patients, but with CHOP’s Clinical In Vivo Gene Therapy group, we also have an amazing infrastructure to support a gene editing clinical trial,” she said. “I can't think of another place in the country that has all of these teams in place, where you can go from proof-of-concept in a cell all the way to treating a patient and have a group of experts who can support you along the way.”