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Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects
Int J Mol Sci. 2020 Dec 29;22(1):273. doi: 10.3390/ijms22010273.
Piter J Bosma1, Marius Wits1, Ronald Pj Oude-Elferink1
1Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AGEM, Amsterdam UMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands.
Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.