Within minutes of KJ Muldoon's birth, doctors knew there was something very wrong. Five weeks premature, his little arms went rigid when lifted and shook oddly on the way back down. An attentive doctor at the University of Pennsylvania, checking for a host of possible causes, noticed that KJ's ammonia level was off the charts. He was rushed across the street to Children's Hospital of Philadelphia, where doctors quickly offered a dire diagnosis. His body couldn't clear ammonia, which is produced when the body turns protein from food into energy. Without being able to urinate it out, like healthy people do, the ammonia would build up and damage first his brain and then his whole body. By day two of KJ's life, his parents Kyle and Nicole were getting the worst possible news: "I heard 'death' or 'severely developmentally disabled.' There wasn't really a whole lot of getting around that," Kyle remembered. Yet nine months later, KJ is smiling, sitting up unassisted and – on one recent day – happily eating avocado. "He's defeated all odds and obstacles so far that were put in his way. He exceeds our expectations," Nicole said in a May 12 call with reporters. All this is possible because KJ is the first-ever recipient of a gene therapy designed to treat only a single person. Every month for the last three, he's received an infusion of billions of tiny balls of fat, containing instructions to edit genes in his liver cells. Fixing the genetic mistake in at least some of his liver cells enables his body to make an enzyme called CPS1, which is needed to break down protein. KJ's ammonia level is now pretty close to normal. Doctors say it's too early to declare KJ "cured" or know what the rest of his life will look like. But he's definitely on a better trajectory than when Nicole and Kyle, who have three older children, were told the best they could hope for was to minimize KJ's suffering. "Seeing him reach milestones that are important for any infant as they're developing blows us away even more because we know what was stacked up against him and how bad of a prognosis it was in the very beginning," said Nicole, 34 of Clifton Heights, Pennsylvania. Long before KJ was born, a team of Penn doctors and researchers had been looking to test a never-before-tried treatment approach. Working through a company he helped found, Dr. Kiran Musunuru, a Penn cardiologist, had figured out how to gene-edit liver cells. In 2021, returning to his lab after the pandemic, Musunuru teamed up with Dr. Rebecca Ahrens-Nicklas, a metabolic physician at Children's Hospital of Philadelphia. The pair hoped to make progress against urea-cycle disorders – inherited metabolic problems, like KJ's that leave young children vulnerable to bursts of damaging ammonia. "I have a whole group of patients who have no options," Ahrens-Nicklas told USA TODAY. Existing medications and diet can help reduce the risk of ammonia overloads and a liver transplant can fix most problems, she said, but the child has to live long enough and grow big enough for a transplant, at about a year. KJ's disease was serious enough that Ahrens-Nicklas wasn't sure he'd make it to his first birthday, or what condition his brain would be in if he did. Even before telling KJ's parents, Musunuru and Ahrens-Nicklas studied whether they might be able to fix his specific genetic mutation with an editingtechnology known as CRISPR. Some mutations remain beyond scientists' current ability to correct. Within a few weeks, Sarah Grandinette in Musunuru's lab had come up with an approach and tested it on mice. But they still had to make the bespoke therapy fast enough to do KJ good – before the ammonia started killing more brain cells. Time was not on their side. By Valentine's Day, they had an approach that worked well enough that the Food and Drug Administration said they could consider giving it to a person. Nicole and Kyle then had a choice to make. They could wait and hope medications could hold off enough damage that KJ would reach his first birthday and be eligible for a transplant. Or they could opt for the gene therapy sooner, theoretically putting him at lower risk both of early brain damage and consequences from the transplant. Plus, he wouldn't need to be on immunosuppressive medication for the rest of his life, as he would with a transplant. But it was an approach that had never been tried on anyone ever before. "I had a very profound feeling about this gene editing, which was such a foreign concept, I mean, still," said Kyle, also now 34. Nicole, who works in education, is the analytical one of the pair, he said. "She takes the pitcher out in the 7th inning. I make decisions off of feel." The extended family and care teams "had some spirited debate" about which would be the best decision, Kyle said, always keeping in mind KJ's comfort. "We prayed, we talked to people, we gathered info, we eventually decided this was the way we were going to go." Still, Feb. 25, the first infusion day, was pretty nerve-wracking, especially for the many doctors who crowded his hospital room. "It was two of the longest hours of my life," Ahrens-Nicklas said. KJ, then nearly six months old, slept through the whole thing. After the second, higher dose, Ahrens-Nicklas said she able to reduce KJ's other medication. She's still waiting to see if the third, even higher dose provided any additional benefit. The lessons doctors are learning on KJ will hopefully be used to help many other children. "The exciting piece here is this may turn out to be the new paradigm for very rare diseases," said Dr. Peter Marks, who ran the division at the Food and Drug Administration that oversaw the development of KJ's personalized treatment. The exact genetic fix will be different for each person, but the approach is very repeatable, said Marks, who has since left the FDA. "Ninety-nine percent is going to be the same whether you're treating this child or another," he said. "This is really exciting because it may give us the roadmap for how to move forward in this rare disease space, very efficiently bringing in long-lasting treatments and potential cures to children who otherwise would never have had any hope of having them." KJ will turn 10 months old on June 1. His doctors and family couldn't be happier. "All the milestones that he's reaching or developmental moments that he's reaching show us that things are working," Nicole said. "The prognosis for him was very different before we started talking about gene editing and infusions." To Kyle, his family's story is one of "inspiration and fate." "This was all meant to happen," he said. There was the luck of Nicole having pregnancy problems that led her to deliver at Penn instead of a hospital closer to home. The doctor who noticed what was going on and quickly got him into treatment. The team that was ready and looking for someone just like KJ. "It just kind of all fell into place to give us this little fighter of a boy that we have," said Kyle, who offered advice for other parents going through a medical odyssey. "Educate yourself on what the child's going through, meet the doctors, learn their names, develop relationships," he said. And most of all, "it's important to find even the tiniest bead of hope and hold onto that as long as you can." This article originally appeared on USA TODAY:First-of-its-kind gene therapy a success against baby's rare disease
