News of the First Personalized CRISPR Gene Editing Therapy
In May 2025, the first patient to be successfully treated with personalized CRISPR gene editing therapy was discharged from the hospital after spending several months there.1,2 The patient had been diagnosed with severe carbamoyl phosphate synthetase 1 (CPS1).
What is CPS1 Deficiency?
Carbamoyl Phosphate Synthetase 1 Deficiency (CPSID) is a rare, genetic metabolic disorder caused by a complete or partial absence of the carbamoyl phosphate synthetase (CPS) enzyme, a protein essential for the urea cycle, the process that removes excess nitrogen from the body. Without CPSI, ammonia builds up in the blood, leading to hyperammonemia. It is one of many Urea Cycle Disorders (UCDs) with CPSID having an estimated incidence rate of 1:1,300,000 and for UCDs it is at least 1:35,000 births.3,4 CPSID can be initially characterized by “the refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Shortly thereafter, affected infants may also experience seizures, respiratory distress, and abnormal movements and postures. The symptoms are mostly attributable to the swelling of the brain (cerebral edema) caused by hyperammonemia.” Children may even lapse into a coma. The condition is inherited in an autosomal recessive pattern (both parents must carry a faulty gene copy) with an estimated mortality rate of 50% in early infancy.5
The Reported Case – and Treatment
When patient KJ, an infant, was admitted to CHOP (Children’s Hospital of Philadelphia) with CPS1 Deficiency, doctors and researchers presented the parents with an unprecedented option. After spending his first few months on a restrictive hospital diet, KJ received doses of his personalized therapy between six and seven months of age, in February 2025. The treatment was administered safely, and he is now growing well and thriving.
Physician Rebecca Ahrens-Nicklas, MD, PhD, from the Metabolic Disease Program and the Division of Human Genetics at the Children’s Hospital of Philadelphia, and researcher Kiran Musunuru, MD, PhD, MPH, ML, MRA, the Barry J. Gertz Professor of Translational Research at Penn’s Perelman School of Medicine, are co-corresponding authors of a recently published paper in this much-needed research field.2,6,7 The paper details how they began collaborating in 2023 to explore the feasibility of developing customized gene editing therapies for individual patients, building on years of research into rare metabolic disorders and the potential of gene editing as a treatment strategy.
They developed a base-editing therapy, delivered in vivo to hepatocytes using lipid nanoparticles, for KJ, who was diagnosed at birth with CPS1 deficiency.2 This work was based on their years of preclinical research with similar disease-causing variants.
A Plan is Formulated and Approved
Initial studies in mice and nonhuman primates received regulatory approval. Then, genome sequencing of the patient and analysis of the father’s blood-derived DNA were conducted under a human subjects research protocol. The timing was urgent, but within two months, researchers had developed a therapeutic cell line to address the deficiency using the base editor k-abe (kayjayguran abengcemeran).
Full details of the cellular studies, animal models, and off-target assessments are available in the supplementary material accompanying the researchers’ brief report published in the New England Journal of Medicine in May 2025.2
An expanded-access Investigational New Drug (IND) application for an individual patient was submitted to the FDA when the patient was six months old and received approval one week later.
An Improved Outcome
After the formulation was approved for the clinical phase, the patient received his first treatments. He responded positively and, as of April 2025, had completed three doses of the therapy without experiencing any serious adverse effects. In the brief period following treatment, he showed improved tolerance to dietary protein and required less use of nitrogen scavenger medications. He was also able to recover from common childhood infections, such as rhinovirus, without developing elevated ammonia levels. While continued monitoring will be necessary to fully assess the long-term effectiveness of the treatment, he was discharged from the hospital and is now at home with his family.
Other Therapeutic Approaches for CPS1 Deficiency
In parallel, small molecule medications are being explored to stabilize mutant CPS1 enzymes, enhance residual enzymatic activity, or act as ammonia scavengers to mitigate toxic accumulation. When combined with CRISPR gene therapy, these complementary approaches hold promise for improving outcomes in patients with severe CPS1 deficiency by targeting both the root cause and its metabolic consequences.
A New Era of Hope for Rare Genetic Disorders
The successful treatment of KJ with personalized CRISPR gene editing therapy marks a historic milestone—not just for CPS1 deficiency, but for the future of precision medicine. This case demonstrates what is possible when scientific innovation, clinical urgency, and compassionate care converge. While much remains to be understood through long-term follow-up, KJ’s progress offers hope to families affected by rare metabolic disorders and lays the foundation for similar individualized treatments. As research advances and complementary therapies are refined, this breakthrough signals the beginning of a transformative new era—one in which a diagnosis of a rare genetic condition may no longer mean limited options, but instead, the potential for tailored, life-changing solutions.
Update
Since this blog was written, the co-leader of the research, Kiran Musunuru, of the University of Pennsylvania, recently presented findings at the European Society for Gene and Cell Therapy. Afterwards, he sat down with Endpoints News for a twenty-five-minute question-and-answer session that touched on the reaction by the medical community towards the research and plans to make more custom drugs in a clinical trial that could begin next year. It can be found here. It is both a compelling and personal perspective on the ramifications and promise of gene editing.