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Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome

ABSTRACT Introduction: The Crigler–Najjar syndrome (CNS) is an ultra-rare recessive disorder of the liver. There is no effective cure, except for liver transplantation, a procedure with many risks and shortcomings. Thus, the development of novel therapeutic approaches is a clinical need. Areas covered: This review aims at describing potentialities and limitations of novel experimental treatments that can be applied to cure the CNS and other metabolic liver diseases. These include pharmacological and gene therapy approaches, some of them are now being applied in clinical trials of Crigler–Najjar patients. Brief descriptions of bilirubin metabolism, mechanisms of disease, and animal models are also included. Expert opinion: AAV-mediated gene therapy approaches to pediatric liver diseases are very challenging due to the potential loss of viral DNA consequent to liver growth. Novel immunomodulatory strategies are being developed that can allow re-administration of the therapeutic vector by blocking the generation of anti-AAV neutralizing antibodies. Another very promising approach is gene targeting of the therapeutic cDNA into a ‘safe-harbor locus,’ resulting in the permanent correction of the genetic defect. However, further experimentation is still required to increase safety and efficacy. The success of these approaches will result in alternative therapies to liver transplantation.