Individualized gene editing: A leap forward in treating rare genetic disorders

Rare diseases are defined as medical conditions affecting fewer than one in 2,000 individuals. Globally, an estimated 300 million people are affected by rare diseases, making them collectively more common than previously recognized. Approximately 80% of rare diseases have a genetic cause, and next-generation sequencing (NGS) has advanced their diagnostics over the past two decades, but about 95% of rare genetic diseases still lack approved therapies. In a landmark study published in the New England Journal of Medicine, researchers from the Children’s Hospital of Philadelphia and the University of Pennsylvania reported in vivo base-editing therapy administered to a neonatal patient with carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an ultra-rare genetic disorder. This individualized gene-editing approach marks a paradigm shift in the treatment of rare genetic diseases.

CPS1 is a mitochondrial enzyme that catalyzes the initial step of the urea cycle, mainly in hepatocytes, by converting ammonia and bicarbonate into carbamoyl phosphate, which is essential for detoxifying harmful ammonia into urea for excretion. Mutations in the CPS1 gene can lead to reduced or absent enzyme activity, resulting in CPS1 deficiency (CPS1D; MIM: 237300), which causes hyperammonemia, liver damage, and encephalopathy characterized by coma if left untreated. Clinically, CPS1D is categorized into neonatal-onset and late-onset forms based on the age of symptom onset. The neonatal-onset form typically presents with hyperammonemic coma and is associated with high mortality, often leading to death within the first week. Individuals who recover from a coma may experience long-term neurological impairments. Current clinical management of CPS1D focuses on controlling hyperammonemia through dietary restrictions, ammonia-scavenging drugs, and, in severe cases, liver transplantation, which remains the only curative option, but irreversible brain damage often occurs before liver transplantation can be performed.

As reported, the infant was diagnosed with CPS1D based on clinical manifestations, hyperammonemia, plasma amino acid profiling, and genetic testing, revealing two truncating CPS1 variants: c.1003C>T (p.Gln335Ter, Q335X) and c.2140G>T (p.Glu714Ter, E714X). Early intervention with continuous renal replacement therapy (CRRT), followed by nitrogen-scavenging medications, citrulline supplementation, and a protein-restricted diet, significantly alleviated symptoms. However, clinical deterioration emerged after 100 days. Confronting a life-threatening condition with no therapeutic alternatives, the research team implemented a personalized “N-of-1” strategy, which refers to an investigational paradigm wherein bespoke therapy is engineered for a single patient following exhaustion of standard treatments.