A team of doctors at Children's Hospital of Philadelphia (CHOP) and Penn Medicine have successfully treated a baby with a rare and deadly genetic disorder using a groundbreaking gene editing approach, potentially opening the door to treating millions of patients with rare genetic diseases.
The infant, KJ Muldoon from Clifton Heights, Pennsylvania, was born with CPS1 deficiency, an extremely rare condition affecting approximately 1 in 1.3 million people. The disorder prevents the liver from producing an enzyme crucial for converting ammonia—a byproduct of normal protein breakdown—into urea for excretion. Without treatment, ammonia accumulates to toxic levels, damaging the liver, brain, and other vital organs.
Pioneering Personalized Treatment
Within just six months of KJ's birth, the medical team developed a custom gene editing treatment specifically designed to correct the mutations in his DNA. The therapy utilizes base editing, a refined version of CRISPR technology that allows scientists to rewrite the genetic code one letter at a time without cutting the DNA strand, reducing the risk of unintended genetic changes.
"This is the first step towards the use of gene editing therapies to treat a wide variety of rare genetic disorders for which there are currently no definitive medical treatments," said Dr. Kiran Musunuru, a University of Pennsylvania gene editing expert who co-authored the study published in the New England Journal of Medicine.
The treatment was delivered through tiny fat particles called lipid nanoparticles, which carry the editing machinery directly to liver cells. KJ received his first infusion in February, followed by additional doses in March and April.
Remarkable Clinical Progress
Prior to treatment, KJ faced a grim prognosis. CPS1 deficiency is fatal in approximately half of affected infants, with liver transplantation being the only established treatment option.
"We were weighing all the options, asking all the questions for either the liver transplant, which is invasive, or something that's never been done before," said Nicole Muldoon, KJ's mother.
Following the treatment, KJ has shown significant improvement. Now 9½ months old, he can eat more normally and has demonstrated better resilience against common illnesses like colds, which typically exacerbate symptoms in patients with CPS1 deficiency. He also requires less medication to manage his condition.
Dr. Rebecca Ahrens-Nicklas, a gene therapy expert at CHOP and study author, noted: "We're still very much in the early stages of understanding what this medication may have done for KJ. But every day, he's showing us signs that he's growing and thriving."
Implications for Rare Disease Treatment
This breakthrough has profound implications for the estimated 350 million people worldwide living with rare diseases, most of which are genetic in nature. Traditionally, developing treatments for rare disorders has been challenging from a commercial perspective, as the small patient populations make it difficult to recoup development costs.
However, the researchers believe their work demonstrates that creating customized treatments doesn't have to be prohibitively expensive. According to Dr. Musunuru, the cost was "not far off" from the $800,000-plus typically required for a liver transplant and related care.
"As we get better and better at making these therapies and shorten the time frame even more, economies of scale will kick in and I would expect the costs to come down," Musunuru explained.
Scientific Innovation and Future Potential
The speed at which the team developed this personalized therapy is particularly noteworthy. Dr. Senthil Bhoopalan, a gene therapy researcher at St. Jude Children's Research Hospital who wasn't involved in the study, called it "very exciting" that the team created the therapy so quickly, adding that "this really sets the pace and the benchmark for such approaches."
The treatment's success builds on years of progress in gene editing technology. The original CRISPR tool, which won its inventors the Nobel Prize in 2020, has evolved into more precise techniques like base editing, which was employed in KJ's case.
Carlos Moraes, a neurology professor at the University of Miami, predicts rapid advancement in the field following this breakthrough: "Once someone comes with a breakthrough like this, it will take no time for other teams to apply the lessons and move forward. There are barriers, but I predict that they are going to be crossed in the next five to 10 years."
A Family's Hope
For Kyle and Nicole Muldoon, both 34, the decision to pursue this experimental treatment came after careful consideration.
"We prayed, we talked to people, we gathered information, and we eventually decided that this was the way we were going to go," Kyle Muldoon said.
Now, they celebrate each of KJ's developmental milestones, no matter how small. "Any time we see even the smallest milestone that he's meeting – like a little wave or rolling over – that's a big moment for us," Nicole shared.
While researchers emphasize that long-term monitoring will be necessary to fully understand the treatment's effects, KJ's case represents a significant step forward in the treatment of rare genetic disorders and offers hope to countless families affected by similar conditions.
The research was funded in part by the National Institutes of Health, highlighting the importance of continued public investment in advancing genetic medicine for rare diseases.
