In Vivo Gene Editing for CPS1 Deficiency: The KJ Case and the First Personalized Liver-Targeted Therapy

The video chronicles the groundbreaking in vivo gene editing treatment for CPS1 deficiency in a newborn nicknamed KJ. Researchers engineered a personalized therapy, KAbe, delivered via IV as tiny lipid nanoparticles that travel to the liver to correct a misspelling in the CPS1 gene. The story covers the diagnosis, design of a patient-specific editing approach, safety considerations, FDA compassionate-use approval, and the patient’s remarkable improvement, including reduced ammonia levels and a return home. It also discusses broader implications for rare diseases, potential applications to other tissues, and the ethical and regulatory challenges of personalized, in vivo gene editing.

Introduction

The video presents the case of a newborn in Philadelphia diagnosed with CPS1 deficiency, a deadly liver enzyme disorder within the urea cycle, for which a liver transplant is often the only cure. A multidisciplinary team seeks to treat KJ with a novel, personalized in vivo gene editing therapy, a first of its kind.

The Disease and the Challenge

CPS1 deficiency arises from misspellings in the CPS1 gene that cripple a liver enzyme, allowing ammonia to accumulate and damage the brain. Standard care involves strict protein restriction and routine liver transplantation, which is difficult in tiny infants due to size and surgical risks. The case emphasizes the urgency and the high stakes of saving a neonate with an ultra-rare condition.

The Therapeutic Breakthrough: KAbe

Researchers design a patient-specific editing drug, KAbe or KAB, to correct the mutation in KJ’s liver cells. The therapy uses an adenine base editor and a bespoke guide RNA targeted to a site on chromosome 2 to convert an A to a G, prompting the cell to restore CPS1 function. KAbe is packaged in extremely small lipid nanoparticles to deliver the editing components to the liver via IV infusion, representing an in vivo approach rather than the traditional ex vivo cell editing.

Technology and Safety

The team creates patient-specific cell lines and mouse models to test the therapy, and conducts toxicology studies in non-human primates and mice to minimize risks such as off-target edits and germline changes. Though there is still risk, the researchers argue that the potential benefit justifies moving forward under compassionate use and an expanded IND application with the FDA.

Clinical Course and Outcome

After starting KAbe, KJ experiences better ammonia control, allowing higher protein intake and reducing the immediacy of a transplant. He receives sequential infusions and eventually goes home, highlighting the potential of in vivo gene editing to transform treatment for rare, lethal genetic diseases beyond CPS1 deficiency.

Broader Impact and Future Prospects

The video discusses how this approach could extend to other liver disorders, blood diseases and cancers, emphasizing personalization as a game changer for ultra-rare conditions. It also outlines challenges in scaling, tissue targeting, and ensuring safety across patients, while noting the ethical considerations and regulatory pathways required to broaden adoption.

Conclusion

The KAbe/KJ case is framed as a landmark demonstration of rapid deployment patient-specific gene editing, with researchers expressing optimism about a future where such therapies become more routine for genetic diseases.