Gene Therapy for Acquired and Genetic Cholestasis

Abstract

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

Keywords: AAV; PFIC; cholestatic diseases; gene therapy.

Figure 1

Genetic classification and pathogenesis of PFIC. The diagrams show the genes and functions altered in each type of PFIC. The main deficient proteins for each type of PFIC are indicated by red crosses, while derived alterations in other proteins or pathways are indicated by blue crosses. Damage due to the abnormal accumulation of BAs is shown as yellow circles with orange lightnings.

Figure 2

Pharmacological treatments for cholestatic diseases. (A) Mechanisms of action of UDCA, which favors the presence of hydrophilic BAs over hydrophobic BAs in bile, decreasing the toxic effect of “detergent bile” in cholestatic patients. (B) NTCP transporter inhibitors block the entry of BAs into hepatocytes. (C) ASBT inhibitors prevent the reabsorption of BAs in enterocytes, decreasing their entrance into the enterohepatic recirculation. Inhibitions are indicated with blue crosses. BA, bile acid (yellow circles).

Figure 3

Gene therapy approaches for acquired cholestatic diseases. Different gene therapy strategies have resulted in an alleviation of liver disorders according to their anti-apoptotic, anti-inflammatory, and anti-fibrotic properties, respectively. Adv, adenoviral vector; AAV8, adeno-associated vector with serotype 8; ACE2, angiotensin-converting enzyme; AQP-1, aquaporin; Cthrc-1, collagen triple helix repeat containing-1; HNF4a, hepatocyte nuclear factor 4 alpha; IGF, insulin-like growth factor; SOD, superoxide dismutase; uPA, urokinase-plasminogen activator. This figure was created using BioRender.com.