Progress and challenges in gene therapy for Crigler-Najjar syndrome

Introduction: Adeno-associated viral (AAV) vector-mediated, liver-directed gene therapy has shown to be feasible and effective to improve coagulopathy in patients with hemophilia B. Inherited severe unconjugated hyperbilirubinemia, known as Crigler-Najjar syndrome (CN), is a suitable disease model for AAV-mediated gene therapy, enabling application of this approach in the near future.Areas covered: This review provides an overview of gene therapy strategies for CN, focusing on AAV vector-mediated gene transfer. Despite good progress, major challenges regarding pre-existing humoral immunity against the vector and the inability to re-administer the viral vector have yet to be overcome. Here we discuss possible solutions for these challenges and cover other emerging therapeutic strategies for liver-directed gene therapy.Expert opinion: Promising results from pre-clinical studies warrant the translation of AAV vector-mediated gene therapy for the treatment of CN toward clinical application. Steps have been taken toward a phase I/II trial, while a screening protocol will reveal the prevalence of pre-existing humoral immunity in the CN patient population. Other emerging gene therapeutic strategies hold great promise, such as targeted genomic integration that may result in a more robust expression of the transgene or ex vivo gene integrating therapy followed by transplantation of the corrected cells. Both approaches still require extensive research before clinical application can be considered. Our focus for the near future rests upon the readily available AAV vector-mediated, liver-directed gene therapy platform for the treatment of Crigler-Najjar syndrome.