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

Table 2 Selected examples of liver-specific gene therapies for viral hepatitides

Disease	Therapy	Rationale	Disadvantages	Stage of development	Ref.
HBV	Expression of anti-HBV primary microRNA (pri-miR)-122- and pri-miR-31-based mimics	Using artificial HBV-targeting pri-miRNAs it was possible to silence viral genes selectively, thus reducing their expression and causing inhibition of viral replication	Expression of pri-miRs must be maintained over prolonged periods	Preclinical	[22]
HBV	Administration of increasing doses of HB-110 DNA vaccine with fixed doses of adefovir dipivoxil	HB-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 HBV	Possibility of escape mutants and viral rebound after therapeutic withdrawal	Clinical (phase I)	[23]
HBV	Administration of a single dose ARC-520 with entecavir	ARC-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-520	The efficacy of RNAi-therapeutics must be maintained over prolonged periods	Clinical (phase IIa)	[24]
HCV	Administration of Miravirsen to target miR-122 with LNA–modified oligonucleotide	miR-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 infection	LNA-oligonucleotide expression needs to be maintained for long periods	Clinical (phase II)	[25]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; RNAi: RNA interference; HBsAg: Hepatitis B surface antigen; LNA: Locked nucleic acid.