Personalized CRISPR therapy for CPS1 deficiency: Clinical results of the world's first case

In 2025, updated clinical data were published on the world's first use of personalized CRISPR-Cas9 therapy in a patient with an extremely rare inborn error of metabolism, carbamoyl phosphate synthetase 1 deficiency (CPS1), a severe disorder of the urea cycle.

CPS1 is a mitochondrial enzyme in hepatocytes that catalyzes the initial and rate-limiting step of the urea cycle. Its deficiency leads to impaired nitrogen utilization and the rapid development of hyperammonemia with severe neurotoxicity. The neonatal form of the disease is characterized by onset in the first days of life with progressive encephalopathy, seizures, and the risk of coma.

The prognosis without effective therapy is extremely poor: high early mortality and severe irreversible neurological sequelae in survivors. Conservative treatment is supportive and does not address the underlying cause of the disease, and liver transplantation remains the only potentially radical, but high-risk, option.
 
In the presented clinical case, the patient received customized CRISPR therapy aimed at correcting a pathogenic variant of the CPS1 gene. The drug was developed and administered at the academic medical center Children's Hospital of Philadelphia (CHOP) as part of a research protocol.

Three treatments were administered to the patient during 2025. The child spent the first ten months of his life in the hospital, after which he was discharged for outpatient observation.

Clinical results by the end of the year:

• stabilization of metabolic control;
• absence of life-threatening hyperammonemic crises;
• possibility of terminating long-term hospitalization.

After discharge, the child celebrated his first birthday at home, began walking independently, and is preparing to celebrate the holiday season outside the hospital for the first time. These changes reflect the sustainability of the achieved clinical effect and a fundamental improvement in the quality of life of the patient and his family.

This case is considered as proof of the fundamental feasibility of personalized "n=1" therapies for ultra-rare diseases with an extremely unfavorable natural history. It simultaneously raises key questions for healthcare systems and regulators—about acceptable models for the development and approval of such drugs, requirements for long-term monitoring, and pharmacovigilance.

Source: Children's Hospital of Philadelphia (https://www.chop.edu/news/kj-stepping-holidays-after-milestone-year)