CHOP and Penn treated an infant with a rare disease by editing his genes

Within hours of his birth last August, Baby KJ was so sick, his parents didn‘t know if he would live long enough to get to play with his three older siblings in Clifton Heights, just outside Philadelphia.

His liver could not process protein, putting KJ at risk of irreparable brain damage. His team of doctors at Children‘s Hospital of Philadelphia and the Hospital of the University of Pennsylvania had few options for treating his rare metabolic disorder, called severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, which is deadly in more than half of cases.

Then his doctors proposed a novel treatment using experimental gene-editing technology: They would analyze KJ’s genetic profile to find the mutation that prevented his body from producing a key enzyme that breaks down protein. Then they would infuse a medication laced with bits of genetic code to find the misspelling and fix it, dramatically improving his chances of recovery.

Within six months, researchers at CHOP and Penn had developed a customized drug specifically for KJ using CRISPR, the buzzy shorthand for a scientific tool that works like a find-and-replace command. It is named after a stretch of genetic code utilized — clustered regularly interspaced short palindromic repeats.

KJ received three doses of the drug between February and April, and his liver function has improved immensely.

The Philadelphia team’s work demonstrates that CRISPR technology can be rapidly developed into personalized treatments for exceptionally rare diseases. Outside experts called KJ’s case, detailed Thursday in the New England Journal of Medicine, a milestone for the technology.

KJ’s medication was customized to his DNA and will never be used for another patient. But the basic formula could be repurposed for other patients.

“This is the future of medicine, a step toward using gene-editing for diseases for which there are few treatments,” said Kiran Musunuru, director of the Penn Cardiovascular Institute’s Genetic and Epigenetic Origins of Disease Program, who coauthored the study, during a call with reporters in advance of the journal article publication.

» READ MORE: What’s next for CRISPR? A Penn cardiologist wants to edit the genes of people with high cholesterol.

Scientific interest in CRISPR has soared over the last decade as an opportunity to systematically engineer therapies for hard-to-treat diseases, from rare genetic disorders to common chronic conditions. Yet advancing gene therapy faces ongoing challenges: Manufacturers are often reluctant to invest in treatments with limited applications, ongoing safety concerns, and eye-popping sticker prices that can climb into the millions for a course of treatment.

CRISPR researchers point to KJ’s experience as an example of the technology’s capabilities. The 9-month-old is now sitting up independently, waving, and eating avocado.

He will need ongoing care, but is meeting milestones his care team was not sure he would ever reach. Before his CRISPR-based treatment, KJ’s best option was a low-protein diet, combined with medications to control his ammonia levels, while he and his family waited to see if he could grow strong enough for a liver transplant.

“It has been an unbelievable transformation,” said Kyle Muldoon, KJ’s father.

CRISPR is a gene-editing tool with an unlikely origin story involving quality-control tests on bacteria used in making yogurt.

Scientists discovered that bacteria keep records of the DNA of viruses that attack them. These microbial “mug shots” can be utilized to pinpoint a genetic misspelling in a patient’s DNA.

A type of enzyme is then used to “cut” the misspelling and either correct it or eliminate it.

As a type of gene therapy — the umbrella term for any gene-based approach to correcting DNA mutations — CRISPR has wide potential to advance medical treatments, from cancer to high cholesterol.

In 2023, the FDA approved the first CRISPR-based therapy for sickle cell disease, a painful disorder caused by misshapen red blood cells. The single-dose infusion medication, Casgevy, reduces the number of sickle-shaped cells.

» READ MORE: The FDA just approved the first gene-editing treatment, and CHOP played a key role

KJ’s treatment was a new application for CRISPR. Doctors used the technology to develop a custom drug using information about his specific gene mutation.

Doctors at Penn and CHOP worked with outside research and manufacturing partners to quickly produce the drug and test it for safety. They were granted expedited authorization by the Food and Drug Administration under rules designed to fast-track treatments for rare diseases.

CRISPR treatments for adults are often administered in a single dose. But KJ’s doctors opted for three smaller doses administered by IV, each slightly larger than the last, to ensure the treatment was safe for such a tiny and fragile patient.

KJ’s first IV infusion day in February was a “terrifying and exciting” two hours, said Rebecca Ahrens-Nicklas, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at CHOP and a collaborator with Musunuru.

“The whole hospital community was rooting for him,” she said.

Meanwhile, KJ was unfazed.

“He slept through the whole thing,” Ahrens-Nicklas said.

After each dose, doctors monitored KJ to see if he was better able to process protein. Without treatment, his genetic disorder would result in dangerously high levels of ammonia, the main byproduct of protein, building in his liver. This can be toxic to the brain and nervous system.

They knew the treatment was working when he was able to eat more protein without his ammonia levels spiking, and started meeting typical baby milestones, like rolling over.

“While KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” Ahrens-Nicklas said.

CRISPR experts acknowledge that to outsiders, treating one child’s extremely rare disease with a gene therapy that is custom to him, and cannot be used on another patient, might not seem practical for widespread application.

But KJ’s drug could be repurposed for other rare diseases, the research team involved said.

Much as a basic bread recipe can be customized, researchers envision that the basic drug formula used for KJ could be kept the same, while personalizing it with information about a new patient’s specific genetic mutation.

“This is proof of concept,” said Petros Giannikopoulos, a pathologist and principal investigator at the Innovative Genomics Institute, a consortium of academic gene-editing centers in California that helped with safety tests for KJ’s drug. “You can make a medicine that’s very specific — even if they’re one in a million — and in a reproducible way.”

That approach could make a notoriously expensive technology more accessible.

Gene therapies can cost millions of dollars for one-time doses. Casgevy has a list price of more than $2 million.

CHOP and Penn researchers said they could not pinpoint a price for KJ’s custom treatment because manufacturing and research partners had volunteered their services.

But they said that the accelerated timeline for developing the drug meant less time and money spent on research, which could make the treatment comparable to the cost of a liver transplant.

Kelly Banas, the associate director of research at ChristianaCare’s Gene Editing Institute, who was not involved in the study or KJ’s care, said she was impressed by how quickly the team worked, with buy-in from research and manufacturing partners, while taking detailed safety steps.

“There’s a bit of a road map now,” she said.

Early signs suggest that KJ’s therapy made his disease more mild, but he is not cured. He has increased his protein intake and decreased medication doses.

His long-term medical needs remain unknown, and he may still need some medications to keep his ammonia levels in normal range, doctors said.

They expect him to leave CHOP within a few weeks.

Kyle and Nicole Muldoon know their youngest son will need ongoing care and monitoring, but they can‘t wait to bring KJ home to be with his three older siblings.

“We’ve seen him hooked up to every monitor, heard every alarm code beep,” Kyle Muldoon said. “We take it one day at a time, and see where it goes.”