KJ Muldoon was born from a catastrophic medical problem. In the race to solve that, doctors may have launched a “roadmap” for a new type of treatment.
A groundbreaking gene therapy trial will restore hearing in young children
The UK gene therapy trial has revived hearings in young children.
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Within minutes of the birth of KJ Muldoon, the doctors knew there was something very wrong.
Five weeks earlier, his small arm stiffened when lifted, shaking strangely along the way.
A polite doctor at the University of Pennsylvania checked many possible causes and noticed that KJ’s ammonia levels were off the charts.
He rushed over the street to Philadelphia Children’s Hospital, where doctors quickly provided a disastrous diagnosis. His body was unable to clear ammonia. Ammonia is produced when the body changes proteins from food to energy. Unable to urinate it, as healthy people do, ammonia accumulates, causing damage to the brain first and then the whole body.
By the second day of KJ’s life, his parents Kyle and Nicole had gotten the worst news: “I heard “death” or “someone with a severe developmental disorder.” There wasn’t much to avoid that,” recalled Kyle.
But nine months later, KJ is smiling and not assisted. “He has beaten all the possibilities and obstacles so far, and that’s what got him in his way. He’s exceeded our expectations,” Nicole said in a May 12 call with a reporter.
All this is possible as KJ is the first recipient of gene therapy designed to treat only one person.
Every three previous months, he has undergone infusions of billions of small fats, including instructions to edit genes into liver cells. Correcting genetic errors at least in some of his liver cells allows his body to make an enzyme called CPS1, which is necessary to break down proteins. The ammonia levels in KJ are now quite close to normal.
The doctor says it’s too early to “heal” KJ or declare or know what the rest of his life will look like. But he is definitely on a better trajectory than when Nicole and Kyle, who have three older children, were told it was best to be to minimize KJ’s suffering.
Nicole, 34, of Clifton Heights, Pennsylvania, said:
Wing experiment
Long before KJ was born, Penn’s team of doctors and researchers was trying to test an unprecedented approach to treatment.
Penn’s cardiologist Dr. Kiran Musnur, who worked through a company he found, found a way to gene-edit hepatocytes.
Back in his lab after the pandemic in 2021, Musnur worked with Dr. Rebecca Arlens Niklas, a metabolic physician at Children’s Hospital Philadelphia.
The pair hoped to make progress against urea cycle disorders. This inherited metabolic problems like KJ, which are vulnerable to young children’s damage ammonia.
“I have an entire group of patients with no choice,” Ahrens-Nicklas told USA Today. Existing medications and diets can help reduce the risk of ammonia overload, and liver transplants can solve most problems, she said, but children must grow large enough for the transplant in about a year.
KJ’s illness was severe enough that Ahrens-Nicklas wasn’t sure he would get it on his first birthday or what state his brain would be like if he did.
Even before speaking to KJ’s parents, Musnur and Arrens Nicklas studied whether editing techniques known as CRISPR could correct specific genetic variation. Some mutations exceed the current ability of scientists to modify.
Within a few weeks, Sara Grandinet from Musnur’s lab came up with an approach and tested it with a mouse. But before ammonia started killing more brain cells, they still had to make a bespoke therapy quickly enough to get the KJ done well. Time was not by 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 people.
Impossible decision
Nicole and Kyle then had the option to choose. They could wait and expect that KJ could reduce the damage enough to reach his first birthday and qualify for a transplant.
Alternatively, they could opt for gene therapy earlier, and in theory he would reduce the risk of both early brain damage and the consequences of transplantation. Furthermore, he does not need to take immunosuppressive medications for the rest of his life, like in transplants.
But it was an approach that no one has ever tried before.
“I felt very deep about this gene editing. It was such a foreign concept, meaning I still said 34.
Nicole, who works in education, is analytical to the pair, he said. “She takes the pitcher out in the seventh innings. I make a decision from the touch.”
With KJ’s comfort in mind at all times, the expanded family and care team were “having some lively discussions,” Kyle said. “We prayed, talked to people, gathered information and finally decided this was the way we went.”
Unique medicine
Still, the first injection date, February 25th, was pretty nervous, especially for many doctors who crowded his room.
“It was two of the longest times of my life,” said Arlens Niklas.
KJ slept throughout the rest of the year, nearly six months later.
After the second high dose, Ahrens-Nicklas said he could reduce other medications in KJ. She is still waiting to see if the third higher dose will bring about additional benefits.
I hope that the lessons that doctors are learning at KJ will be used to help many other children.
“The exciting piece here may turn out to be a new paradigm for very rare diseases,” said Dr. Peter Marks, who ran the department of the Food and Drug Administration, which oversaw the development of KJ’s personalized treatments.
The exact genetic modifications vary from person to person, but the approach is highly repeatable, Marks said.
“99% is the same as whether you’re dealing with this child or another child,” he said. “This is really exciting because it could provide a roadmap for how to move forward in this rare disease space, so we can bring long-term and potential treatments to children who would otherwise not have wanted to have them.”
Hope for the future
KJ will be 10 months old on June 1st. His doctors and his family were not happy.
“Every milestone he’s reaching or the developmental moment he’s reaching indicates that things are working,” Nicole said. “His prognosis was very different before I started talking about genetic editing and injection.”
For Kyle, his family story is one of “inspiration and destiny.”
“This was all meant to happen,” he said. Nicole is lucky enough to have pregnancy problems, which led her to give birth in a pen instead of a hospital close to her home. The doctor realized what was going on and immediately led him to treatment. A team looking for someone ready and like KJ.
“It just fell into that place to give us this little fighter of the boy we have,” Kyle said.
“Educate yourself about what your child is going through, seeing doctors, learning names, and building relationships,” he said. And most importantly, “It’s important to find the smallest beads of hope and hold them as much as possible.”
