Personalized Gene Editing Therapy Treats Rare Disease: Pennsylvania Infant Becomes First Case

(Image courtesy of The Associated Press)

Gene editing technology has made groundbreaking strides in the medical field in recent years, particularly in the treatment of rare genetic disorders. According to a study published in The New England Journal of Medicine on May 15, 2025 (DOI: 10.1056/NEJMoa2504747), a newborn in Pennsylvania became the world’s first patient to receive personalized gene editing therapy for a rare disease.

An infant named KJ Muldoon was diagnosed shortly after birth with an extremely rare genetic disorder—carbamoyl-phosphate synthetase 1 (CPS1) deficiency. This metabolic disease, which affects the urea cycle, has an incidence rate of only 1 in 1.3 million and carries an estimated 50% mortality rate in early infancy.

CPS1 Deficiency

CPS1 deficiency impairs the urea cycle, leading to dangerously high ammonia levels in the blood, which can cause neurological damage or death. Within 48 hours of birth, KJ exhibited symptoms such as lethargy and respiratory distress, with blood ammonia levels exceeding 1000 μmol/L (normal range: 9–33 μmol/L). Traditional treatments, including nitrogen-scavenging medications (e.g., glycerol phenylbutyrate), citrulline supplementation, and a strictly protein-restricted diet, can only temporarily manage symptoms but cannot cure the disease. Additionally, infants are often too small to undergo liver transplantation, the only long-term solution. However, KJ’s parents refused to give up and sought alternative treatments, ultimately following the advice of doctors at the Children’s Hospital of Philadelphia (CHOP) to try personalized gene editing therapy.

Personalized Gene Editing Therapy

The research team developed a therapy called k-abe, which utilizes adenine base editing technology delivered via lipid nanoparticles to repair the Q335X variant in liver cells. The therapy was designed within two months of KJ’s birth and validated for safety and efficacy in cynomolgus monkeys and mouse models. After receiving approval from the U.S. Food and Drug Administration (FDA) and CHOP’s ethics committee, KJ received intravenous infusions of k-abe at doses of 0.1 mg/kg and 0.3 mg/kg at approximately 7 months (day 208) and 8 months (day 230) of age, respectively.

Over the 7 weeks following treatment, KJ showed significant clinical improvements:

• Increased Protein Intake: KJ was able to consume more dietary protein, at times exceeding the recommended daily intake for his age, without needing a strictly protein-restricted diet.

• Reduced Nitrogen-Scavenger Dosage: The dose of glycerol phenylbutyrate was reduced from 10.1 ml/m²/day to 5.0 ml/m²/day, with no significant adverse effects.

• Stability During Viral Infections: During treatment, KJ experienced two viral infections with vomiting and diarrhea but did not develop hyperammonemic crises, a stark contrast to his pre-treatment condition.

• Decreased Ammonia Levels: Blood ammonia levels dropped from a median of 23 μmol/L before treatment to 9–13 μmol/L post-treatment, indicating treatment-related improvement.

• Changes in Urinary Orotic Acid Levels: Urinary orotic acid levels rose from 1.7 mmol/mol creatinine (low end of normal range) to 2.4–2.6 mmol/mol creatinine (high end of normal range or slightly elevated), suggesting partial restoration of CPS1 function.

KJ’s weight increased from 7.14 kg (9th percentile) before treatment to 8.17 kg (26th percentile) after 7 weeks, with stable neurological status and no serious adverse events reported.

This study brings new hope to patients with rare diseases. Although the short follow-up period limits evaluation of long-term efficacy and further observation is needed, personalized gene editing therapy holds promise for application to other genetic metabolic disorders, marking a significant milestone in rare disease treatment. The research team’s ability to complete the process from diagnosis to therapy development in just 6 months demonstrates the immense potential of gene editing technology in addressing urgent medical needs. As the technology matures, this rapid and precise treatment approach is expected to offer hope to more patients with rare genetic disorders.

Reference：

• Musunuru, K., Grandinette, S. A., Wang, X., Hudson, T. R., Briseno, K., Berry, A. M., Hacker, J. L., Hsu, A., Silverstein, R. A., Hille, L. T., Ogul, A. N., Robinson-Garvin, N. A., Small, J. C., McCague, S., Burke, S. M., Wright, C. M., Bick, S., Indurthi, V., Sharma, S., … Ahrens-Nicklas, R. C. (2025). Patient-specific in vivo gene editing to treat a rare genetic disease. New England Journal of Medicine. Advance online publication. https://doi.org/10.1056/NEJMoa2504747

• AP News