ATP8B1 deficiency: Steps towards personalized therapy

ATP8B1 deficiency is an autosomal recessive liver disease caused by mutations in the ATP8B1 gene. Clinical symptoms range from intermittent (benign recurrent intrahepatic cholestasis; BRIC) to progressive intrahepatic cholestasis (progressive familial intrahepatic cholestasis; PFIC). Medical therapy of the more severe phenotype (PFIC) is rarely effective, necessitating invasive therapies like liver transplantation. For this group of patients, the development of new treatment options, including targeted compounds for mutation-specific therapy, is essential. In this thesis, total biliary diversion was introduced as a safe and effective symptomatic treatment option for certain patients with severe ATP8B1 deficiency. In addition, aberrant pre-messenger RNA splicing was established as one of the underlying disease mechanisms of ATP8B1 deficiency and we demonstrated that modified U1 small nuclear RNAs are able to rescue several of these splicing defects very efficiently in vitro. Furthermore, we identified six compounds that could rescue the defective plasma membrane targeting of p.I661T-ATP8B1 in vitro. With the data presented in this thesis important steps were taken towards a more personalized treatment strategy for ATP8B1 deficiency.