*1.2. Presentation and Current Treatment*

All forms of PFIC present with jaundice and elevated bile acid levels in serum [1]. The disease onset varies between the different types of PFIC. ABCB11/BSEP (PFIC2), TJP2 (PFIC4) and FXR (PFIC5) deficiency, present in the first months after birth and are rapidly progressing. Presentation of ATP8B1 deficiency (PFIC1) is often months after birth and the progression is moderate. Both other forms, ABCB4 (PFIC3) and MYO5B (PFIC6) deficiency, are diagnosed at a later more variable age with moderate to slow progression [1]. Upon diagnosing cholestasis; serum parameters, liver biopsies and genetic analyses are all used to identify the genetic cause of cholestasis. For instance, high gamma GT is only seen in ABCB4 deficiency (PFIC3) [12] while FXR deficiency results in persistent increased Alpha FetoProtein (AFP) levels in serum [6]. Liver biopsies can be used to verify the absence of proteins involved in physiologic bile formation in the canaliculi or other mechanisms like intracellular protein accumulation that cause hepatocyte and cholangiocyte damage. Identification of the cause allows treatment to begin, albeit all current treatments for PFIC, at best, only slow down disease progression. Ursodeoxycholic acid (UDCA) treatment, reducing the hydrophobicity of the bile salt pool, is a first treatment option for all types of PFIC. The efficacy of this treatment depends on the type of mutation, with patients having missense mutations showing a better response compared to those with complete deficiency [5,13]. In patients with missense mutations in the *ATP8B1* or the *ABCB11* gene, that affect protein folding, 4-phenylbutyrate, restored presence of these transporters in the canalicular membrane, albeit at a low level [14–16]. Symptoms are mitigated by a reduction in the bile salt pool by biliary diversion or by preventing intestinal uptake by binding of bile acids to cholestyramine [1]. The efficacy and safety of pharmacological inhibition bile acid uptake using inhibitors of the apical sodium dependent bile transporter (ASBT) may be another approach to reduce the bile acid pool [17,18]. Diarrhea is an adverse effect of several of these approaches due to increasing amounts of bile acids reaching the colon. In view of this, FXR activation to lower bile acid synthesis in the hepatocytes maybe an option to overcome this hurdle and in combination with ASBT inhibition could be an effective approach [19,20]. Several of these treatments do relieve the symptoms and slow disease progression but none of these is curative. For the more recently identified genetic causes of PFIC, namely TJP2-, FXR- and MYO5B-deficiency no treatment options have been reported [1].

This lack of effective treatment options results in disease progression in all patients suffering from PFIC. Upon reaching end-stage liver disease, a liver transplantation is needed for patient survival.

Progress in the performance of liver transplantations over the past decades has led to an established, albeit highly invasive, procedure called orthotopic liver transplantation (OLT) [21]. Long-term complications consist of graft loss and an increased risk for infections and cancer development due to immunosuppressive treatment. The early severe liver damage in many patients suffering from PFIC renders liver transplantation during childhood necessary. This procedure has become the standard of care to treat children with end-stage liver disease with a 20 year survival of over 80% [22,23]. Partial liver transplantation improves size matching between grafts and recipients and alleviates the shortage of size matched donor livers without compromising survival [24]. In addition, this also allows living family-related donor transplantations.

For all severely affected patients, a liver transplant is currently the only curative therapy which has been successfully performed in children suffering from PFIC [25]. Additional complications of this major procedure were also reported in these patients. Patients with mutations that completely abolish ATP8B1 function developed hepatic steatosis in the donor liver. This can be prevented when combining the liver transplant with total internal biliary diversion, but extrahepatic symptoms like severe diarrhea persist [2,25,26]. Also in patients with FXR deficiency complications occurred upon transplantation, these patients also developed a fatty liver [1]. In patients with ABCB11 (BSEP) deficiency, the cholestasis symptoms re-occurred after OLT due to an immune response inhibiting BSEP function [27].

These additional complications, the lack of sufficient donor organs, the risk of lifelong immune suppression to prevent organ rejection, and an increased risk for infection and cancer, warrant the development of novel treatment options for these devastating diseases. Gene therapy seems one of the potential treatments for these monogenic recessive disorders.
