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

Abstract

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.

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

“…Gene therapy: The additional complications associated with LT warrant the consideration of innovative therapeutic modalities like gene therapy. Recent approval for Adenovirus Associated viral (AAV) vector-based gene therapy for other monogenic disorders, raises hope for such future therapies for PFIC[ 68 ]. The liver tropism of AAV vectors is a major advantage in the treatment of PFIC as this would imply the need for a lower vector dose for therapeutic efficacy.…”

“…Higher AAV vector doses have been shown to cause adverse effects ranging from transient liver inflammation to even progressive liver failure and deaths in few reports[ 69 ]. Gene therapy can be non-integrating where each cell division post therapy will lead to some loss of episomal AAV vector genome or integrating in vivo where these integrated genes are copied during cell division and passed on to the daughter cells without any loss of vector genome upon cell division[ 68 ]. The benefit of integrating gene therapy is that a limited number of corrected hepatocytes will repopulate the liver and correct the defect[ 68 , 70 ].…”

“…Gene therapy can be non-integrating where each cell division post therapy will lead to some loss of episomal AAV vector genome or integrating in vivo where these integrated genes are copied during cell division and passed on to the daughter cells without any loss of vector genome upon cell division[ 68 ]. The benefit of integrating gene therapy is that a limited number of corrected hepatocytes will repopulate the liver and correct the defect[ 68 , 70 ]. Theoretically, in vivo non-integrating AAV mediated gene therapy can be successful in PFIC3 as establishing ABCB4 expression in a proportion of hepatocytes.…”

“…Treatment with modified mRNA variants encoding human ABCB4 encapsulated in lipid nanoparticles lead to de novo expression of functional ABCB4 and restored phospholipid transport in cultured cells as well as Abcb4-/-mice. Hepatocyte damage due to accumulated BA in PFIC1 and 2; and decreased membrane stability in PFIC1 would warrant the correction of the genetic defect in all the hepatocytes, thus needing an integrating gene therapy strategy[ 68 ]. Tumor genes is a possible major risk factor with integrating gene therapy as seen in trials on patients with severe combined immunodeficiency[ 72 ].…”

A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector

“…However, this promoter is very large (> 2.4 kb) [ 13 ] significantly limiting its use in the context of some gene therapy vectors such as those derived from adeno-associated virus (AAV) which have a small packaging capacity [ 14 ]. Thus, a smaller promoter with the same functionality would represent an attractive approach for the development of AAV-based gene therapy vectors expressing genes involved in BA homeostasis, many of which have a very large size [ 15 ].…”