For the first time, doctors have treated a baby born with a rare, life-threatening genetic disorder with a gene-editing therapy scientists tailored to specifically repair his unique mutation.
The baby received three infusions containing billions of microscopic gene-editors that homed in on a mutation in his liver and appear to have corrected his defect. Doctors need to follow the boy longer to determine how well the treatment is working. But so far the bespoke therapy appears to have at least partially reversed his condition, reducing his risk of suffering brain damage and possibly even death.
"It's really exciting," says Dr. Rebecca Ahrens-Nicklas, an assistant professor of pediatrics and genetics at the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania who treated the child. "He's a pioneer."
Ahrens-Nicklas and her colleagues described the case Thursday in The New England Journal of Medicine and at a meeting of the American Society of Gene & Cell Therapy.
"This shows the potential — that we can really open the door for these transformative treatments for patients who really have no other options," Ahrens-Nicklas told NPR in an interview. "It really is sort of limitless in terms of what the possibilities are."
The child's parents are thrilled for their son, KJ Muldoon, who was born at CHOP in August.
"Seeing him reach milestones that are important for any infant as they're developing blows us away," says Nicole Muldoon, 34, who lives in Clifton Heights, Pa., with KJ, her husband, Kyle, and their three other children.
Doctors have started using gene-editing treatments like CRISPR to treat devastating genetic blood disorders such as sickle cell disease, and are studying experimental gene-editing therapies for other diseases, including cancer, inherited high cholesterol and some forms of genetic blindness.
But doctors, many patients and their families have been frustrated because pharmaceutical companies don't have a strong economic incentive to develop gene-editing treatments for extremely rare disorders, even though altogether millions of babies are born each year with thousands of conditions that potentially could be cured by editing their genes.
In response, scientists have been trying to solve the problem by developing a template for groups of rare conditions that are similar enough that a gene-editing treatment for one could be easily adapted for others. That way each case wouldn't have to go through a long regulatory approval process, which could make it much less expensive and practical.
"This is an important first step towards an entirely new type of personalized medicine. I think it's going to utterly transform the way we practice medicine, particularly in the area of rare diseases," says Dr. Kiran Musunuru, a professor for translational research at the University of Pennsylvania, who worked with Ahrens-Nicklas on KJ's case. "I think this is the future of modern medicine."
Anytime scientists test a highly experimental treatment on a patient for the first time, it raises sensitive questions, especially when the patient is a child and especially when patients or families are desperate. But two independent bioethicists who reviewed the case for NPR say the researchers appear to have taken the proper precautions.
"It is very exciting, and may be a real step forward," provided the doctors discussed the possibility of a liver transplant instead with KJ's parents, says Dr. Lainie Ross, director of the University of Rochester School of Medicine and Dentistry's Center for Bioethics.
"Many ethical issues were indeed clearly and carefully addressed," agrees Laurie Zoloth, a University of Chicago bioethicist.
In an editorial accompanying the study, a former high-ranking Food and Drug Administration official says the approach "could be transformational."
"Although not all rare diseases may be eligible for a gene-editing approach with available technology, there could be hundreds to thousands of diseases that could be treated through an approach similar to the one described," wrote Dr. Peter Marks, who recently was forced out of the agency.
In another article accompanying the report, Andrea Gropman at the St. Jude Children's Research Hospital and Alexis Komor of the University of California, San Diego, say much more research is needed to answer many open questions, including how long the treatment may last.
"Longer-term follow-up of this patient will be critical to obtaining answers," they wrote.
Muldoon's treatment came after Musunuru, Ahrens-Nicklas and an international collaboration of researchers had tried to develop a gene-editing therapy for six other children born with rare diseases before KJ. But those attempts took too long to help.
When KJ was born, he seemed fine. But then his doctors quickly realized he was in trouble.
"One of the doctors came to us and said: 'We think we know what's wrong. Your son is very sick,' " says Kyle Muldoon, KJ's father.
Turned out, KJ was born with carbamoyl phosphate synthetase 1 (CPS1), an inherited genetic disease known as a urea cycle disorder. The condition causes toxic levels of ammonia to build up in a child's body whenever they eat protein, making them prone to brain damage and possibly even death.
CPS1 patients can be treated with drugs to reduce ammonia in their bodies and minimize the damage, but the treatment may only be partially effective. Patients can sometimes get a liver transplant, but only if they find a donor and not until they are a year old. By that time, many have suffered irreversible brain damage. So KJ's doctors knew time was of the essence.
"Every day that passed there was another risk that he could have neurologic injury from an elevated ammonia episode," Ahrens-Nicklas says.
The team finally succeeded, creating a gene-editing therapy using a technique known as "base-editing," that was targeted specifically for KJ's genes.
"Because we had spent so much time doing these dress rehearsals, we actually had gotten pretty good at doing this," Musunuru says. "We had a solution in hand several weeks after birth."
After the FDA agreed to make an exception from standard testing requirements and let the researchers try the treatment for KJ on an emergency basis, the doctors offered it as an option to the baby's parents.
"Our child is sick. We either have to get a liver transplant or give him this medicine that's never been given to anyone before," Kyle Muldoon says. "What an impossible decision to make."
The Muldoons decided to gamble on something that had never been done before. Both the Muldoons and the doctors were on edge the day of the Feb. 25 treatment.
"The first time you're putting a new drug into a baby is scary," says Ahrens-Nicklas. "No one has done this before. No one has developed a personalized gene-editing therapy for an infant. It was quite a nerve-wracking but exciting day. And it was quite a momentous day."
Everyone was relieved when the baby slept peacefully through the two-hour infusion. The microscopic gene-editors zeroed in on one of KJ's mutations so tiny molecular scissors could perform a kind of genetic surgery — literally rewriting his genetic code to fix his defect.
"This is an encouraging sign to us," Ahrens-Nicklas says.
The treatment has also allowed his doctors to reduce by half the medication he needs to help rid his body of dangerous ammonia.
"It's one of those watershed moments in medicine," says Fyodor Urnov, scientific director of the Innovative Genomics Institute at the University of California, Berkeley, who was part of the team that developed the treatment for KJ.
"Ultimately we hope this has set a precedent where we have firmly entered a world of genetic cures — CRISPR cures — on demand. I think we can say: This is the year when CRISPR-on-demand is truly born."
The hope is this approach will not only enable scientists to produce gene-editing treatments much more quickly but also far less expensive. The researchers said they couldn't estimate the cost of treating KJ because it was part of a research project.
Others agree.
"I think it's wonderful to have the potential technology to address patients for whom there is no off-the-shelf treatment," says Dr. Edward Neilan, the chief scientific officer at the National Organization for Rare Disorders. "This is very significant."
KJ's parents describe seemingly small but crucial clues to the benefits their son seems to be experiencing.
"Even today, he's eating avocado. And we were like, 'We never thought that this was going to happen,' " Nicole Muldoon says. "I walked in today and he's sitting upright all by himself in a crib. And we didn't even know if that was going to be something he was going to be able to do independently."
"He sailed through beautifully. He had no complications from it," Ahrens-Nicklas says.
The first infusion, which was a very low dose designed to minimize any risks, didn't have much of an effect. So doctors gave KJ two more. And those appear to be working without producing any side effects, his doctors say.
He can eat more protein and has been gaining weight, they say.
The hope is this approach will not only enable scientists to produce gene-editing treatments much more quickly but also far less expensively. The researchers said they couldn't estimate the cost of treating KJ because it was part of a research project that was supported by the National Institutes of Health.
Their son is also waving and rolling over on his own — more milestones no one knew would ever be possible, she says.
"That's big for us," Nicole Muldoon says.
But Ahrens-Nicklas is being cautious.
"We have made real progress and right now the signs are promising," she says. "But we're still in early days right now."
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