An infant named KJ has made history as the first patient to be treated with an in vivo CRISPR gene editing therapy designed specifically for him.
After displaying symptoms of a rare metabolic disease just after birth, scientists raced to prepare a custom CRISPR therapy to correct the genetic mutations causing KJ's illness. After receiving three ascending doses of the therapy when he was about six months old, KJ is now on a reduced medication regimen, can eat a more normal diet and is hitting developmental milestones.
His condition was initially so severe that if a doctor hadn’t noticed something was wrong right away, “he wouldn’t have made it to day five,” KJ’s mother Nicole Muldoon said during a May 12 press briefing.
The results of KJ’s treatment were published in the New England Journal of Medicine on May 15. Funding for the work came primarily from the National Institutes of Health.
KJ, soon to be 10 months old, was born with inherited genetic mutations that cause a urea cycle disorder called carbamoyl phosphate synthetase 1 (CPS1) deficiency, which is when patients lack an enzyme important for processing ammonia during protein digestion. Without enough of this enzyme, ammonia builds up to toxic levels, threatening serious brain injury and death.
KJ's personalized therapy was designed and administered by a vast team of collaborators led by pediatrician and metabolic disease expert Rebecca Ahrens-Nicklas, M.D., Ph.D., and cardiologist and Verve Therapeutics co-founder Kiran Musunuru, M.D., Ph.D., both of the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania.
Typically, patients with CPS1 deficiency can experience vomiting, lethargy and coma. Patients have to avoid protein in their diet, use dialysis to purge ammonia from their bodies and regularly take medications to replace the function of the missing enzyme. The only long-term fix is a liver transplant, which is extremely risky for a critically ill infant like KJ, Ahrens-Nicklas said in the briefing.
Though KJ was born with two gene variants that contribute to his disease, the researchers chose to focus on the variant Q335X, which doesn't make any CPS1 enzyme and therefore does nothing to help the body clear ammonia, according to Ahrens-Nicklas.
First of its kind
While others have used gene editing to craft personalized therapies, KJ’s treatment is the first custom-built CRISPR therapy meant to directly fix a disease-causing mutation in his genome.
“As soon as KJ was born, we had a patient who was facing a very, very devastating outcome, and in real time, with the clock ticking, we were able to make a therapy for him within several months,” Musunuru said in the briefing.
“What we've done here,” he added, “I'm absolutely certain is unprecedented.”
In 2022, scientists from PACT Pharma led a small trial to remove T cells from patients with cancer, engineer them with CRISPR and then infuse them back into patients to target each patient’s specific disease. This gene editing occurred outside of the patients’ bodies, and did not permanently alter their genomes the way KJ’s is designed to.
And in 2023, scientists attempted to use a personalized CRISPR-based therapy to boost gene activity in a patient with Duchenne muscular dystrophy. The goal here wasn’t to edit the genome itself but to tweak how a gene was being expressed. The patient ultimately passed away eight days after treatment due to an immune reaction and later cardiac arrest.
Though KJ is doing much better than his initial prognosis, Ahrens-Nicklas doesn’t call him cured—in fact, she doesn’t ever use the word “cure” at all.
“We're still very much in the early stages of understanding what this medication may have done for KJ,” she said. "But every day he's showing us signs that he's growing and thriving."
KJ will likely live with a milder form of his disease going forward, Ahrens-Nicklas explained, and the team will continue monitoring his development and studying the effects of his unique treatment.
“We have more to learn from him,” Ahrens-Nicklas said. “Knowing KJ, he's probably going to prove everyone wrong every single step of the way.”
Becoming the standard of care
Musunuru believes that in a “couple of generations, gene editing therapies will have become the standard of care for many diseases,”—just as routine as antibiotics or blood pressure medications.
The cardiologist has worked for years to develop liver-targeting gene therapies that can lower cholesterol as a way to tackle heart disease. The biotech he co-founded, Verve, has several pipeline programs designed to tweak cholesterol-raising genetic variants to healthier versions using in vivo gene editing.
Around 2021, Musunuru became interested in using the liver-targeting approach for other diseases caused by genetic mutations and reached out to Ahrens-Nicklas because of her expertise in metabolic conditions.
“A lot of her patients have misspellings that result in broken enzymes or even missing enzymes in the liver, which means they can't process nutrients or clear toxins from the body properly,” Musunuru explained in the briefing.
After first tackling a more common—but still rare—metabolic disease, Ahrens-Nicklas realized the approach could work for her sickest patients. About two years ago, the two started developing a process to edit extremely rare mutations that cause the more serious urea cycle diseases, which includes CPS1 deficiency.
“We started working with known genetic changes previously seen in patients with either PKU or urea cycle disorders, doing practice runs to figure out how to streamline the process,” Musunuru said. “When KJ was born, we were ready.”
Still, time is everything when it comes to treating such serious diseases, and Musunuru wants to get the process down to weeks instead of months.
When it comes to cost, gene therapies are often expensive to develop, in part because of the time it takes to test the therapies for safety and efficacy, Musunuru said.
Because of KJ’s dire situation, the FDA approved his experimental treatment plan after one week of review, and the treatment’s development was aided by donated labor from Acuitas Therapeutics, Integrated DNA Technologies and Aldevron, among others. This made the process significantly cheaper than it otherwise would have been.
Outside of KJ’s unique case, Musunuru expects personalized gene editing to get cheaper over time.
“As we go forward and as we get better and better and better in doing this, economies of scale will kick in, and I think you can expect the cost to come down additional orders of magnitude,” he said.
Going home
The next step in KJ’s treatment journey is for him to do something he’s never done before—go home. KJ has lived at the hospital since he was born last year, which has kept him away from his three older siblings and required his parents to essentially live part-time at CHOP.
“We're going to continue to see how he does in terms of his ability to take protein in his diet, to be able to wean down his medications,” Ahrens-Nicklas said. “As we prepare him for home, we're really excited about making all those steps in his journey.”
KJ’s progress now—including sitting up on his own, waving and rolling over—starkly contrasts with the prognosis his parents Nicole and Kyle Muldoon received before the gene therapy treatment was administered.
“They said this could get to a point where we have to talk about comfort care,” Kyle recalled during the briefing, with Nicole clarifying that this meant end-of-life, palliative care.
“Every day we get with him,” Kyle said, “we are unbelievably blessed.”