On 15 May 2025, researchers from Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at

University of Pennsylvania (Penn), USA, announced, at a meeting of the American Society of Gene andCell Therapy, New Orleans, their unprecedented success in treating an infant with a rare and life-threatening genetic condition, carbamoyl phosphate synthetase 1 (CPS1) deficiency, by timely and precisely customized gene editing therapy.

CPS1 deficiency is an extremely rare autosomal-recessive inborn error of metabolism affecting the urea cycle, wherein the liver is unable to fully break down protein byproducts, resulting in the accumulation of ammonia. It has a high mortality (almost 50%) in infancy, and survival hinges on a low-protein diet, supporting therapy with nitrogen scavenger medications, renal replacement therapy, etc., till the child is old enough for a liver transplant. Even so, during this waiting period, there is a high chance of brain damage, coma, and other morbidities.

The team of researchers led by Dr Kiran Musunru and Dr Rebecca Ahrens-Niklas sprang into action in a race against time and treated the infant, Baby KJ, in a remarkably innovative manner by making targeted nucleotide-level base editing correction within the living cells in vivo. In contrast to traditional gene therapy that inserts copies of functional genes carried by vectors into the recipient, they aimed to correct the defective DNA in situ and thus avoided insertion of exogenous genetic material. They accomplished this by using technology based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). Within 2 months of the diagnosis of the condition in the infant, the team developed a patient-specific cell line. It generated a mouse model based on the identification of the most precise base editing approach required for the specific mutation. They developed patient-specific adenine base editors and guide RNAs (as is done in CRISPR technology) for targeting the exact locus of defect on the gene. A lipid nanoparticle-based vehicle was utilized for infusing the guide RNA dose. With ethical and regulatory approvals, including the investigational new drug approval from the Food and Drug Administration, USA, and after testing in non-human primates and mouse models, the first dose was administered as an intravenous infusion to Baby KJ in the 7th month of life, and the second dose in the 8th month. Protein tolerance improved after the first dose of infusion, and further so after the second dose. No serious adverse events occurred. However, the researchers caution that longer follow-up is warranted to assess safety and efficacy.

It is also worth noting that the precision delivery vehicle was designed to deliver customized therapeutic RNA edits to the target organ, specifically liver cells, and potentially avoid affecting germline cells. This addresses an important ethical concern regarding gene editing therapy. The kind of vehicle (lipid nanoparticles) and intravenous administration gives the option of administering further doses should the need arise.

The work was supported by a grant for the somatic cell genome editing programme from the National Institutes of

Health, and also by in-kind contributions from industry and other agencies reflecting public-private partnerships towards the advancement of modern genetic therapeutics.

This achievement of customized/personalized gene editing therapeutics, in successfully treating the hitherto untreatable genetic condition in humans, with such speed and precision, has the potential to change the management of patients with rare genetic conditions significantly.

JYOTI NATH MODI, Bhopal, Madhya Pradesh

ORCID iD: 0000-0002-0626-1637