Two-step AAV8 gene delivery in a child with Crigler-Najjar syndrome type I

Crigler–Najjar syndrome type I, an orphan UTG1A1 enzyme deficiency, manifests at birth with severe unconjugated hyperbilirubinemia. Here we describe sustained clinical response in a pediatric patient with Crigler–Najjar syndrome type I treated with two consecutive doses of AAV8 delivering the UTG1A1 coding sequence. Infusion I (6 × 1012 vg/kg) afforded sustained decrease in serum bilirubin, allowing substantial relaxation of the phototherapy from 12 h to 4 h daily. Infusion II at a double dose was made in 6 months; the decision was intended at complete elimination of phototherapy. However, the elimination led to a sharp increase in bilirubin levels necessitating resumption of phototherapy. The patient is currently stable on 4 h daily phototherapy for 80 weeks since the resumption and 107 weeks since the AAV8 therapy initiation. No toxic side effects were encountered. A slow incremental dynamics in serum bilirubin opens the issue of clinical advisability for subsequent infusions of the drug.