Scientists develop personalized gene treatment for a baby

In August 2024, KJ Muldoon was born, and at a week old, it was discovered that he had a rare genetic disorder called carbamoyl phosphate synthetase 1 (CPS1) deficiency, which is also known as urea cycle disorder. Only one in 1.3 million babies are born with CPS1 deficiency, which causes toxic levels of ammonia to build up in a child's body whenever they eat protein.

Half of all babies with CPS1 die within their first week of life. Children who do survive have several mental and developmental delays and eventually need a liver transplant.

At the Children's Hospital of Philadelphia (CHOP), doctors put KJ on a diet that severely restricted protein and treated him with a medicine called glycerol phenylbutyrate to help remove ammonia in his blood. However, KJ was still at high risk for brain injury or death and lived under 24-hour care at the hospital.

Soon after KJ was born, Rebecca Ahrens-Nicklas, director of the Gene Therapy for the Inherited Metabolic Disorders Frontier Program at CHOP, reached out to Kiran Musunuru, a gene-editing researcher at the University of Pennsylvania, about potentially creating a gene editor to help treat KJ's condition.

Previously, Musunuru, Ahrens-Nicklas, and an international collaboration of researchers had worked on developing a gene-editing therapy for six other children born with rare diseases. However, it took too long to create these treatments.

Although it can take years to develop a gene-editing treatment, KJ had potentially only as little as six months before experiencing an increased risk of severe brain damage or death. "At this point, the clock starts in my mind," Musunuru said. "This is real life. This is not hypothetical."

Working quickly, Musunuru reached out to Fyodor Urnov, the scientific director of the Innovative Genomics Institute at the University of California, Berkeley, to make sure there were no other unexpected or deleterious gene edits elsewhere in KJ's DNA. Several companies, including Aldevron, Integrated DNA Technologies (IDT), Acuitas Therapeutics, and Danaher Corporation, also joined the project, helping to provide different aspects of the new treatment.

According to TIME, Aldevron produced the gene therapy product that combined the RNA genetic sequence targeting KJ's mutation with guide RNA from IDT that directed the CRISPR gene-editing technology to the right genetic sequence in KJ's liver cells. A lipid nanoparticule from Acuitas delivered the treatment.

"[S]cientists burned a vat of midnight oil on this the size of San Francisco Bay," Urnov said, adding that "such speed to producing a clinic-grade CRISPR for a genetic disease has no precedent in our field. Not even close."

Twenty-two days later, doctors gave him a second dose of the treatment. During this time, KJ experienced a few viral illnesses, which would have normally led to severe surges in his ammonia levels, but "he sailed through them," Ahrens-Nicklas said. He was also able to halve the dose of the medication to reduce his ammonia levels.

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According to Ahrens-Nicklas, it's still too soon to tell how effective the CRISPR therapy is, but the medical team is monitoring different metrics, including KJ's ammonia levels and measures of certain amino acids, to ensure that KJ is still healthy.

"We don't know how much benefit KJ received from this [therapy]," Ahrens-Nicklas said. "But the early signs are that he is probably a little more mild than he was going into [this treatment]. He had the most severe form of the most severe urea cycle disorder, and he is doing better at this point than we anticipate for someone with the most severe form of [this disease]."

Going forward, Ahrens-Nicklas and Musunuru say they plan to learn from KJ's case, with a goal of scaling up the platform to address other genetic disorders and shorten the time it takes to create a customized genetic therapy.

"I don't think I'm exaggerating when I say that this is the future of medicine," Musunuru said. "This is the first step toward using gene-editing therapies to treat a wide variety of rare genetic diseases for which there are currently no definitive medication treatments and in some cases, no treatments in development at all."

"We are showing it's possible to make a personalized gene-editing therapy for a single patient in real time, and hope it inspires others to do the same," he added. "Some day, no rare disease patient will die prematurely from a misspelling in their genes that we are able to correct."

In an editorial that accompanied the research, Peter Marks, who previously oversaw gene therapy regulation at FDA, said the method used to create KJ's custom treatment "is, to me, one of the most potentially transformational technologies out there."

The technique used to create KJ's custom treatment could be adapted and used to mix mutations in other places in a person's DNA. Only the CRISPR instructions that lead the editor to the location on the DNA would need to be changed. This allows gene-editing treatment to be cheaper "by an order of magnitude at least," Marks said.

"It's one of those watershed moments in medicine," Urnov said. "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."