In a world-first, researchers designed, tested, and delivered a personalized CRISPR therapy to an infant with a fatal urea cycle disorder.¹ The treatment specifically targeted a rare mutation in the carbamoyl phosphate synthetase 1 (CPS1) gene, was delivered using lipid nanoparticles, and demonstrated early clinical benefit, including enhanced protein tolerance and improved metabolic stability.¹ Published in The New England Journal of Medicine, this breakthrough, led by researchers from the Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, demonstrates the potential of gene editing in treating ultra-rare diseases and underscores a promising future for genomic medicine.^1,2

Neonatal-onset CPS1 deficiency is a devastating inborn error of metabolism that causes severe hyperammonemia within days of life.^3,4 With an estimated incidence of just 1 in 1.3 million births and a 50% mortality rate in early infancy, CPS1 deficiency poses an urgent and unmet therapeutic challenge.^1,3,4 Even with ammonia-lowering drugs, protein restriction, and round-the-clock monitoring, many infants succumb or suffer irreversible neurologic damage before reaching transplant eligibility.^3,4 Until recently, the field lacked any viable approach for rapid, curative therapy tailored to a patient’s unique genetic makeup.⁴

For the first time, a multidisciplinary team leveraged programmable base-editing technology to treat a child carrying two truncating CPS1 mutations.¹ The results showcase not only a scientific achievement, but a complete reimagining of therapeutic timelines for ultrarare genetic conditions.¹ Upon diagnosis, the patient was found to carry two pathogenic variants: Q335X and E714X.¹ The team designed a therapeutic base editor using a novel adenine base editor (ABE) paired with a patient-specific guide ribonucleic acid (RNA).¹ Because CPS1 is primarily expressed in hepatocytes, the editing machinery was packaged into lipid nanoparticles (LNPs), allowing targeted in vivo delivery to the liver.^1,4

Within weeks, the base editors were screened in vitro using human liver cells and custom-engineered mouse models, followed by safety testing in nonhuman primates.¹ By month five, a clinical-grade batch of the therapy—dubbed kayjayguran abengcemeran (or k-abe)—was ready for administration.¹ Regulatory review was fast-tracked under a single-patient expanded-access Investigational New Drug (IND) application, and the patient received two intravenous infusions, at 7 and 8 months of age.¹ Following the second k-abe administration, the patient showed measurable biochemical and functional improvements.1 Dietary protein intake—once severely limited— was increased to above the age-based recommended dietary allowance (RDA).¹ The dose of nitrogen-scavenger drug glycerol phenylbutyrate was also able to be reduced by 50% of the starting dose, and blood ammonia levels stabilized at a median of 13μmol/L (down from 23μmol/L pre-treatment).¹ Additionally, two post-treatment viral illnesses that might previously have triggered metabolic crises were managed without hyperammonemia, hospitalization, or regression in nutritional status.¹ Urinary orotic acid levels, typically low in CPS1 deficiency, rose to the normal-to-high range after treatment—an indirect signal of restored urea cycle activity.¹

While liver biopsy was not pursued due to procedural risk in the infant, the clinical trajectory strongly supports the effective editing of hepatic CPS1 alleles.¹ To minimize immune response to full-length CPS1 protein, prophylactic immunosuppression was employed with tacrolimus and sirolimus.¹ The steroid-sparing approach was crucial, as corticosteroids themselves can precipitate hyperammonemia in CPS1 deficiency.1 This modular platform, relying on shared delivery and editing components with customized guide RNAs, suggests a path forward for scalable, patient-specific gene therapies targeting a wide array of hepatic monogenic diseases.¹

In conclusion, this first-in-human application of CRISPR base-editing for a single patient may foreshadow a broader shift in how clinicians approach rare, life-threatening genetic disorders.¹ By demonstrating that bespoke therapies can be developed, validated, and deployed in a matter of months, this case challenges the traditional timelines and economic models of drug development.¹ It also brings hope to families of children affected by hundreds of other ultrarare metabolic conditions.^1,2 As multidisciplinary teams continue to build clinical and regulatory frameworks for personalized medicine, what was once an aspirational “moonshot” may soon become standard care.^1,2,4

In an interview with Omnihealth Practice, Professor Datuk Dr. A. Rahman A. Jamal, a prominent leader in biomedical research and Project Leader of The Malaysian Cohort—one of Asia’s largest population-based biobanks—shared his insights on the growing role of gene-editing technologies in rare disease management and the promise of precision medicine.

Q1: In your view, how has gene-editing technology changed the landscape of rare disease treatment, particularly in Asia?

Prof. A. Rahman: Gene editing, especially base editing and CRISPR technologies, is allowing us to go beyond symptom control to directly address the genetic root of disease. It is transformative. We are now seeing case studies where life-threatening conditions are stabilized with personalized interventions. In Asia, where access to rare disease treatment varies widely, these technologies offer both opportunities and challenges. With the right systems in place, we could significantly improve outcomes for patients with previously untreatable conditions.

Q2: What would you consider a meaningful clinical outcome when evaluating new therapies for genetic or metabolic disorders?

Prof. A. Rahman: In clinical genetics, success is not just biochemical normalization. It is about whether the patient can thrive, avoid hospitalizations, and have better quality of life. If a therapy helps a child tolerate a normal diet or reduces medication dependency, it is significant. These functional improvements are especially important in pediatric populations, where early gains often translate into long-term developmental benefits.

Q3: As genomic capabilities grow across Asia, how can healthcare systems ensure these advances translate into equitable, ethical access to personalized therapies?

Prof. A. Rahman: The region has made strong progress with mature biobanking and sequencing technologies in place. The next challenge is translating that infrastructure into clinical application. This will require a multidisciplinary collaboration model, along with investment in manufacturing platforms, regulatory frameworks, and trained clinical teams. Importantly, regulatory agencies should be involved early in the translational process to accelerate review timelines and streamline ethical approvals. At the same time, we must prioritize equity and public trust—ensuring that access extends to the wider population and that long-term safety monitoring, especially for off-target effects, is in place.