World-first CRISPR gene editing therapy personalised for an individual patient

Foundational research from team at Children’s Hospital of Philadelphia and Penn Medicine demonstrates power of customised gene editing therapy

In a landmark medical advance, a child – called only ‘KJ’ – with the rare genetic disorder severe carbamoyl phosphate synthetase 1 (CPS1) deficiency has been treated by a personalised use of CRISPR gene editing technology at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine, in the United States. The patient was born with the rare urea cycle disorder which is characterised by build-up of extremely high blood ammonia levels when the CPS1 enzyme is not produced by the liver. 

CPS1 is an enzyme and when normally expressed converts ammonia – a byproduct of protein metabolism – into carbamoyl phosphate. This then continues through the urea cycle culminating in excretion as urea in the urine. It is the first, and rate-limiting, step of the urea cycle, the pathway by which the body uses to remove excess nitrogen, which comes from the breakdown of protein.

After spending their first several months of life in the hospital – on a restricted, low-protein diet – the infant received their first dose of the bespoke therapy in February 2025 when they were aged between six and seven months. Following treatment, the infant has been growing well and thriving.

CRISPR – which stands for ‘Clustered Regularly Interspaced Short Palindromic Repeats’ – is the gene editing therapy that can correct disease-causing variants in the human genome by precisely replacing sections of DNA. 

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Up until now gene editing technology has been used to target more common diseases that affect tens or hundreds of thousands of patients. Two such diseases – sickle cell disease and β-thalassemia – have had a therapy, Casgevy, approved by three major regulatory agencies, the FDA in the US, the EMA in the European Union and the MHRA in the UK, which was the first approval given, in November 2023.

But few diseases benefit from this ‘one-size-fits-all’ methodology to gene editing since very many disease-causing variants can exist. 

“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 that they will prove to be the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” said Dr. Rebecca Ahrens-Nicklas, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at Children’s Hospital of Philadelphia and an assistant professor of Paediatrics in the Perelman School of Medicine at the University of Pennsylvania.

The case of KJ has been reported in a study published by The New England Journal of Medicine. This landmark finding could provide a pathway for gene editing technology to be successfully adapted to treat individuals with rare diseases for whom no medical treatments are available.

Ahrens-Nicklas and Dr. Kiran Musunuru, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine – both corresponding authors on the paper – began studying the feasibility of customised gene editing therapies for individual patients in 2023, as CRISPR technology was gaining traction.

KJ’s specific variant of CPS1 was identified soon after birth, and within six months the team had designed and manufactured a CRISPR base-editing therapy delivered via lipid nanoparticles to the liver in order to correct the faulty enzyme. 

KJ received their first infusion of this experimental treatment in late February 2025. Subsequent follow-up doses were given in the following March and April. As of April, this year, KJ had received three doses of the therapy with no serious side effects. In that time, an increase of dietary protein has been well tolerated and there has been less need for nitrogen scavenger medication, such as sodium benzoate. 

Furthermore, they have also been able to recover from typical childhood illnesses like rhinovirus without resulting in ammonia build up in the body. To fully evaluate the benefits of the therapy longer follow-up will be needed.

“While KJ will need to be monitored carefully for the rest of their life, our initial findings are quite promising,” Ahrens-Nicklas said.

“We knew the method used to deliver the gene-editing machinery to the baby’s liver cells allowed us to give the treatment repeatedly. That meant we could start with a low dose that we were sure was safe,” added Ahrens-Nicklas.

“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. 

“We were very concerned when the baby got sick, but they just shrugged the illness off,” he added.

“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,” he added.

Treatment for CPS1 deficiency has, up until now, been through liver transplant. For patients to receive a liver transplant, they need to be both medically stable and old enough to undergo a major surgical procedure. 

Until that time, episodes of high ammonia build up can risk patients’ health with ongoing, lifelong neurologic damage or, at worst, be fatal. Consequently, the team worked to develop new ways to treat patients who are too young and small for transplant procedures to be considered.

“With KJ, we wanted to figure out how we were going to get the right support. And how we were going to get to the point where they could [be well enough] do all the things a normal kid should be able to do,” said Nicole Muldoon, the child’s mother. 

“It was our responsibility to help our child, so when the doctors came to us with their idea, we put our trust in them in the hopes that it could help not just KJ but other families in our position.”

The research was supported in part by grants from the US National Institutes of Health (NIH) to develop and safely deliver the personalised gene editing therapy. The treatment of KJ is the first time the technology has been successfully deployed to treat a human patient; the technological platform that has developed can be adapted to treat a wide range of genetic disorders. It opens the possibility to create personalised treatments in other organs of the body. 

This is the first known case of a personalised CRISPR therapy administered to a single patient. It was carefully designed to target non-reproductive cells so changes would only affect the patient.

“As a platform, gene editing – built on reusable components and rapid customisation – promises a new era of precision medicine for hundreds of rare diseases, bringing life-changing therapies to patients when timing matters most. Early, fast and tailored to the individual,” said Dr. Joni L. Rutter, director of NIH’s National Center for Advancing Translational Sciences (NCATS).

The work was announced at the American Society of Gene & Cell Therapy meeting on 15 May, 2025 and published as a paper in The New England Journal of Medicine.

NIH, the US' medical research agency, and includes 27 institutes and centres and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical and translational medical research. It is investigating the causes, treatments and cures for all disease. For more information about NIH and its programmes, visit www.nih.gov.

Funding for this project was provided by the NIH Common Fund Somatic Cell Genome Editing program grants, U01TR005355, U19NS132301, U19NS132303, DP2CA281401, and National Heart, Lung, and Blood Institute grants R35HL145203 and P01HL142494. In-kind contributions for the study were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation. Additional funding was provided by the CHOP Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program.

For further reading please visit: 10.1056/NEJMoa2504747