CRISPR base editing treats baby born with rare metabolic disease

A baby born with a rare genetic liver disease has received the world's first customised experimental treatment that involved directly repairing his DNA to fix a faulty protein.

The baby was born with a unique mutation in the gene encoding the CPS1 enzyme, which leads to toxic accumulation of protein waste products from digestion. The rare metabolic disease, known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, results in death in half of those affected. Using a personalised approach to CRISPR/Cas9 genome editing, researchers replaced the solitary mutated DNA base (or 'letter') with the correct one in the baby's individual liver cells, with the aim to restore his protein digestion system with the newly produced enzyme.

''While [the patient] will need to be monitored carefully for the rest of his life, our initial findings are quite promising,' said Dr Rebecca Ahrens-Nicklas, co-corresponding author of the paper published in the New England Journal of Medicine and clinician-scientist at the Children's Hospital of Philadelphia, Pennsylvania, where the baby was treated. 'We hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient's needs.'

Although a similar base editing method to correct a genetic variation that causes lung disease has been trialled in nine adult patients (see BioNews 1282), this was the first reported use in a single individual with a personally-characterised variant.

The patient was identified with a specific variant of the CPS1 gene soon after birth. The team at the Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, subsequently designed and manufactured a base editing therapy specific to the patient's genetic variant.

After approval by the US Food and Drink Authorisation, the treatment was administered when the patient was six months old, intravenously in a lipid nanoparticle containing RNA – which included a specific adenine base editor and a guide RNA that directs the base editor to the location of the gene encoding the CPS1 enzyme. The patient received higher follow-up doses at age seven and eight months.

CPS1 enzyme deficiency, due to any mutation type, affects around one in 1,300,000 babies. The only treatment available is a complete liver transplant, but only if the baby survives until the minimum age eligibility.

Even though the treatment was administered safely, and no serious side effects reported, the team acknowledge the short follow-up as a limitation of the study and that longer follow-up is needed to fully assess the safety and efficacy of the therapy.

'He's received three doses of the therapy without any complications, and is showing some early signs of benefit,' Dr Ahrens-Nicklas told MIT Technology Review, but warned 'It's really important to say that it's still very early, so we will need to continue to watch [him] closely to fully understand the full effects of this therapy.'

Furthermore, Dr Alena Pance, senior lecturer in genetics at the University of Hertfordshire, who wasn't involved in the research, highlights the need to measure what proportion of the patients liver has been genetically corrected: 'This is very important because this will determine the level of physiological improvement of the disease, hence also the value of the intervention.'

Millions of patients worldwide are affected by rare genetic diseases. The accompanying journal editorial described how many of these rare genetic diseases could be treated through a similar approach: 'That is, the combination of rapid diagnosis though genome sequencing and expedited individualised product development, followed by administration of the therapy and careful monitoring of safety and efficacy outcomes'.

First author, Professor Kiran Musunuru from the University of Pennsylvania said: 'We want each and every patient to have the potential to experience the same results we saw in this first patient, and we hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life.'

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The availability of genetic and genomic testing for people and families affected by rare disease will be discussed at the free-to-attend online event Rare Disease Genomic Testing: How Do We Make Access Equitable and Timely?, taking place online on Wednesday 22 October 2025.

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