Review
Copyright ©The Author(s) 2015.
World J Hepatol. Apr 28, 2015; 7(6): 859-873
Published online Apr 28, 2015. doi: 10.4254/wjh.v7.i6.859
Table 1 Selected examples of liver-specific gene therapies for complex genetic and hereditary monogenic disorders
DiseaseTherapyRationaleStage of developmentRef.
Gene therapy for complex genetic diseases
Hepatocellular carcinomaRecombinant human adenovirus type 5 administration followed by TACEAdenovirus is highly infectious and when it is used in conjunction with TACE it improves tissue penetration and thus tumor shrinkageClinical (phase I and II)[18]
Gene therapy for hereditary monogenic diseases
Crigler-Najjar syndrome type IAAV neonatal mouse hUGT1A1 gene transferAAV has low immunogenicity and is highly infectious in hepatocytes. Thus, in this study expression of bilirubin UDP glucuronosyl-transferase was augmented a large number of hepatocytes following transduction with hUGT1A1Preclinical[19]
Familial hyper- cholesterolemiaHepatocytes corrected with retroviruses expressing the low-density lipoprotein receptorThe transplantation of hepatocytes allows the slow repopulation of the liver with a desirable phenotype. In this study this method was used to introduce hepatocytes expressing the low-density lipoprotein receptorClinical (phase I)[20]
Hemophilia ARecombinant factor VIII fused to Fc domain of IgG1 (rFVIIIFc)Coagulation factor replacement therapy requires the regular replacement of factor VIII (FVIII) with recombinant FVIII products or plasma-derived concentrates. The use of a long-lasting recombinant FVIII protein would reduce the need for frequent injections. The fusion of the human Fc domain of IgG1 to FVIII extends the half-life of FVIII and may reduce the injection frequency by 50% when compared with current treatmentsClinical (phase III)[21]
Table 2 Selected examples of liver-specific gene therapies for viral hepatitides
DiseaseTherapyRationaleDisadvantagesStage of developmentRef.
HBVExpression of anti-HBV primary microRNA (pri-miR)-122- and pri-miR-31-based mimicsUsing artificial HBV-targeting pri-miRNAs it was possible to silence viral genes selectively, thus reducing their expression and causing inhibition of viral replicationExpression of pri-miRs must be maintained over prolonged periodsPreclinical[22]
HBVAdministration of increasing doses of HB-110 DNA vaccine with fixed doses of adefovir dipivoxilHB-110 is a DNA vaccine used in chronic hepatitis B infections. This vaccine induces antigen production and stimulates the immune response; helping to clear infected cells from the liver. Adefovir dipivoxil is a chemical therapeutic which blocks reverse transcriptase preventing viral replication. When used in conjunction, adefovir dipivoxil prevents viral replication and thus infection of healthy hepatocytes while the stimulated immune system clears infected hepatocytes, thus reducing the symptoms of chronic HBVPossibility of escape mutants and viral rebound after therapeutic withdrawalClinical (phase I)[23]
HBVAdministration of a single dose ARC-520 with entecavirARC-520 is an RNAi therapeutic that will be used in combination with the inhibitor of HBV DNA polymerase, entecavir, in patients with chronic HBV infection. The decline of HBsAg along with other measures will be evaluated to determine the efficacy of treatment in response to a single dose of ARC-520The efficacy of RNAi-therapeutics must be maintained over prolonged periodsClinical (phase IIa)[24]
HCVAdministration of Miravirsen to target miR-122 with LNA–modified oligonucleotidemiR-122 expression is specific to the liver and plays an important role in the regulation of HCV replication. Disrupting miRNAs can be difficult but one of the tools used to silence their activity are LNA-modified oligonucleotides. Their bridge modification significantly increases their hybridization properties, making disassociation more difficult. In this study they produced a LNA-oligonucleotide which is complementary to miR-122, inhibiting its activity; this decreases HCV replication and reduces infectionLNA-oligonucleotide expression needs to be maintained for long periodsClinical (phase II)[25]