Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects

• Published in: International journal of molecular sciences 2020-12, Vol.22 (1), p.273
• Main Authors: Bosma, Piter J, Wits, Marius, Oude-Elferink, Ronald Pj
• Format: Article
• Language: English
• Subjects: AAV; ABC transporter; Alleles; Animal models; Animals; Bile; Bilirubin; Biopsy; Cholestasis; Cholestasis, Intrahepatic - genetics; Cholestasis, Intrahepatic - therapy; Clinical trials; Clinical Trials as Topic; Disease Management; Disease Models, Animal; Expression vectors; Gallbladder diseases; Gene therapy; Gene Transfer Techniques; Genetic Predisposition to Disease; Genetic Therapy - methods; Genetic Vectors - genetics; Graft rejection; Hemophilia; Humans; Lecithin; Liver; Liver diseases; Liver transplants; Muscular dystrophy; Mutation; PFIC; Phosphatidylcholine; Proteins; Review; Salt; Transplantation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22010273

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. Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.