Genetic Therapies Bootcamp: Foundations, Frontiers, and Clinical Engagement OnDemand-03-10 13-45 318-323 Ahrens-Nicklas Session 2 Gene Editing, CPS1 Deficiency

03-10 13-45 318-323 Ahrens-Nicklas Session 2 Gene Editing, CPS1 Deficiency

Video Transcription

Video Summary

Dr. Aarons Nichols, a clinical geneticist at Children's Hospital of Philadelphia, discussed liver-directed gene editing using lipid nanoparticles (LNPs) carrying RNA molecules that guide genome editing. Collaborating with adult cardiologist Kiran Musunuru, they used base editing—a precise method avoiding double-stranded DNA breaks—to correct genetic mutations. Their work focused on treating liver-related diseases like phenylketonuria (PKU) and urea cycle disorders (UCDs), where liver cells uptake LNPs efficiently. They developed a personalized therapy for an infant with CPS1 deficiency, a severe UCD lacking effective treatments, achieving notable improvements after a one-time IV dose, followed by additional dosing under careful monitoring. Off-target effects were minimized and monitored using the patient’s genome sequence. The case showed the potential of rapid, programmatic gene editing but highlighted challenges: safety, ethical considerations, delivery limitations outside the liver, and the need for new clinical trial models and equitable access. Transparency and collaboration remain crucial as the field advances toward scalable treatments for rare genetic diseases.

Keywords

liver-directed gene editing

lipid nanoparticles

base editing

phenylketonuria

urea cycle disorders

CPS1 deficiency