Personalized gene editing scaled up after record-fast therapy for baby KJ
Late last year, researchers spanning thousands of miles collaborated in an urgent effort to save a single infant. Their work produced a world first: a bespoke base-editing therapy created for one patient and manufactured in a record six months. Now the team that treated baby KJ Muldoon is preparing a clinical trial to treat at least five more children — and to do it faster.
What the trial will test
The follow-up study, described on 31 October in the American Journal of Human Genetics, will use base editing — a CRISPR-derived technique that enables precise, single-letter changes in DNA — to correct mutations that impair the body’s ability to process ammonia. The trial will enroll children with pathogenic mutations in one of seven genes, including CPS1, which is critical for removing toxic ammonia formed during protein breakdown.
How the approach is personalized
The team plans to reuse nearly all of the same base-editing components used for KJ’s therapy and change only the short guide RNA sequence that directs the editor to each child’s specific DNA mutation. Because the guide RNA is the only component that must be tailored, the researchers expect to shorten manufacturing time: from six months for KJ’s bespoke therapy to roughly three or four months for subsequent patients.
“Developing KJ’s treatment was a pretty hectic and intense six months,” says Kiran Musunuru, a cardiologist at the Perelman School of Medicine at the University of Pennsylvania. “But I think we can get it shorter.”
Regulatory precedent and wider impact
Under standard practice, the US Food and Drug Administration (FDA) would expect each new formulation to undergo separate clinical testing and toxicity assessments. In this case, the FDA has indicated it will accept some safety data from KJ’s treatment, easing the pathway for closely related personalized formulations. The investigators are publishing much of their written correspondence with the FDA to serve as a transparent blueprint for other teams.
Fyodor Urnov of UC Berkeley’s Innovative Genomics Institute, who helped develop KJ’s therapy, calls the effort “a textbook example of a ‘rising tide that lifts all boats.’” Still, how broadly the approach can be scaled remains uncertain: Musunuru says the FDA might consider approving the therapy after roughly five to 15 treated children, but a regulatory submission would require an industry sponsor.
About KJ and CPS1 deficiency
KJ was born with a mutation that prevented production of the normal form of carbamoyl phosphate synthetase 1 (CPS1), a liver enzyme that detoxifies ammonia. If ammonia accumulates it can damage the brain; many children with CPS1 deficiency do not survive long enough to receive a liver transplant, the current established cure. In late February, KJ received a bespoke base-editing therapy that corrected a single incorrect DNA base in his CPS1 gene. After treatment his blood ammonia fell and his medication needs were reduced. He has since reached developmental milestones such as standing, starting solids and working toward his first steps.
Outlook
Momentum is building in the field: the Center for Pediatric CRISPR Cures (UC Berkeley and UCSF) aims to develop personalized gene-editing treatments, and the US agency ARPA-H has announced funding to support precision genetic-medicine development and manufacturing. Researchers caution that personalized gene editing is not a universal solution and will require systems for rapid, safe manufacture and industry partners to advance broader regulatory approvals. Still, patient advocates and scientists say the approach could revolutionize treatment options for rare genetic diseases.
Key facts: CPS1 deficiency affects roughly one in a million births; the trial will reuse base-editing components and change guide RNA to match each mutation; FDA has agreed to accept some safety data from KJ’s case; production time may fall to 3–4 months for subsequent patients.
