In a major breakthrough, a patient has been treated with a personalized CRISPR therapeutic that aims to cure their rare genetic disease. This individual, who is known as KJ, was diagnosed with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency at one day old. CPS1 is a rare metabolic disorder in which patients must be placed on a highly restrictive diet to prevent serious health problems from arising. The first CRISPR treatment was administered in February 2025, when KJ was between six and seven months old. So far, the patient is doing very well. The work has been reported in The New England Journal of Medicine. It may help open the doors for open patients with genetic disorders to be treated with CRISPR.
CRISPR is a gene editing tool that relies on several things: an enzyme that can cut the genome, a guide RNA molecule that shows the DNA-cutting enzyme where to go, and sometimes, a template that can be used to repair genetic problems that are in the target sequence. Although this technology has shown huge promise, there has been some concern about how safe it is, and whether it will lead to unintended genetic edits or effects.
But CRISPR has been used successfully to treat adults with sickle cell disease and beta thalassemia. Scientists were interested in applying the technology to treat other disorders, and in a more tailored approach. KJ was transferred to the Children's Hospital of Philadelphia (CHOP) soon after diagnosis, and began treatment.
“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” said Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at CHOP, among other appointments.
Co-corresponding study author authors Ahrens-Nicklas and Kiran Musunuru, MD, PhD have been focused on treating urea cycle disorders. Ammonia is a natural byproduct of protein breakdown in the body. It is usually converted to urea and excreted in urine. But patients with urea cycle disorder cannot convert ammonia to urea because they don't produce a particular enzyme. Ammonia builds up, which can be toxic, and may lead to organ damage.
The researchers aimed to treat a variant of CPS1 that KJ has, which is caused by a genetic mutation. They delivered lipid nanoparticles to the liver in order to correct KJ’s faulty enzyme with genetic edits in late February 2025.
There were follow-up doses in March and April 2025, which KJ has tolerated well. He has taken less medication and has been able to recover from typical childhood infections. The researchers are hopeful that this therapeutic has been effective and safe, but KJ will be evaluated indefinitely.
“While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising,” Ahrens-Nicklas said.
“We want each and every patient to have the potential to experience the same results we saw in this first patient, and we hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life,” Musunuru said. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”
Usually CPS1 deficiency patients need a liver transplant, and they still have to deal with the disorder before they receive one, if they are eligible. So this approach could be life-changing for some people.
Sources: Children's Hospital of Philadelphia (CHOP), The New England Journal of Medicine