Gene therapeutic approaches to inhibit hepatitis B virus replication

Table 1 Advances in hepatitis B virus infection gene therapy in chronological order

Year	Strategy	Milestone	Ref.
1990	AS-ODN	First in vitro application	[22]
1992	AS-ODN	First non-viral transfection (targeted polycation peptide complex)	[28]
	Ribozyme	First in vitro application	[44]
1993	AS-ODN	First in vivo application	[26]
	DNA vaccination		[75]
1994	Dominant negative mutants	First in vitro application	[65]
1997	AS-ODN	First viral transduction (retroviral)	[39]
	Ribozyme		[46]
1998	DNAzyme	First in vitro application	[60]
	EGS		[87]
2001	CTVI		[69]
2003	RNAi	First in vitro application	[93]
		First in vivo application	[94]
2004	Ribozyme	First in vivo application	[56]
	DNA vaccination	First clinical trial in chronic HBV carriers	[81]
2008	CTVI	First in vivo application	[72]
2010	ZFN	First in vitro application	[138]
2011	RNAi	First clinical trial in chronic HBV carriers	[117]
2013	EGS	First in vivo application	[89]
	TALEN	First in vitro/vivo application	[146]
2014	CRISPR/Cas9	First in vitro/vivo application	[148]

AS-ODN: Antisense oligonucleotides; HBV: Hepatitis B virus; EGS: External guide sequence; CTVI: Capsid-targeted viral inactivation; RNAi: RNA interference; ZFN: Zinc finger nuclease; TALEN: Transcription activator-like effector nuclease; CRISPR: Clustered regularly interspaced short palindromic repeats; Cas9: Cas9 nuclease.