Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases

Table 1 Selected examples of liver-specific gene therapies for complex genetic and hereditary monogenic disorders

Disease	Therapy	Rationale	Stage of development	Ref.
Gene therapy for complex genetic diseases
Hepatocellular carcinoma	Recombinant human adenovirus type 5 administration followed by TACE	Adenovirus is highly infectious and when it is used in conjunction with TACE it improves tissue penetration and thus tumor shrinkage	Clinical (phase I and II)	[18]
Gene therapy for hereditary monogenic diseases
Crigler-Najjar syndrome type I	AAV neonatal mouse hUGT1A1 gene transfer	AAV 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 hUGT1A1	Preclinical	[19]
Familial hyper- cholesterolemia	Hepatocytes corrected with retroviruses expressing the low-density lipoprotein receptor	The 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 receptor	Clinical (phase I)	[20]
Hemophilia A	Recombinant 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 treatments	Clinical (phase III)	[21]

TACE: Trans-catheter arterial chemoembolization; AAV: Adeno-associated virus; UDP: Uridine 5’-diphospho.