Gene therapy for liver regeneration: Experimental studies and prospects for clinical trials

Table 1 General characteristics of most commonly used vectors

System	Size of insert (kb)	Infect non-dividing cell	Genomic integration	Duration of expression	Immune response
Adenovirus
1st generation	5	Yes	No	3-4 wk	High
2nd generation	8	Yes	No	Longer with Immuno-supression	High
Gutless	35	Yes	No		Less
Adeno-associated virus	< 4.8	Yes	Yes and episomal	Long-term	Low
Herpes simplex virus 1	35	Yes	No	Long	High
Retrovirus	≤ 8	No	Yes, random	Long-term	Low
Lentivirus	≤ 8	Yes	Yes, into active genes	Long-term	Low
Baculovirus	> 20	Yes	No	Transient	Low
Plasmid-naked	Large	Yes	No	Short	Low
Plasmid-polymer	Large	Yes	No	Short	Low
Plasmid-lipid (liposomes)	Large	Yes	No	Short	Low

Table 2 Main features of reported gene therapy experiments[39,44-50,80-96]

Vector, Ref.	Dose	Transgene (promoter)	Liver model, animals, route	Measured parameters
Adenovirus vector
Hogaboam et al[80], 1999	1 × 108 pfu	r-MIP-2	Acetaminophine injury, mice, IV	↑DNA synthesis, ↑survival
Phaneuf et al[46], 2000	1-4 × 1011 vp	h-HGF (CMV)	Healthy, mice, IV	↑DNA synthesis, ↓apoptosis and ALT
Shiota et al[39], 2000	1 × 109 pfu	r-HGF (CAG)	AAF/70% PH, rats, IV	↑Oval cell proliferation
Nomi et al[95], 2000	1 × 109 pfu	r-HGF (CAG)	D-Gal/LPS liver failure, rats, IP	↓Apoptosis, ↑survival
Hecht et al[48], 2001	1 × 108 TU	h-HIL-6 (CMV)	D-Gal liver failure, mice, IP	↑Survival, ↑proliferation
Hwang et al[81], 2003	1 × 1011 vp	h-HGF (CMV)	TAA liver failure, mice, IV	↑Survival, ↑DNA synthesis, no hepatic necrosis
Iwaki et al[49], 2003	2 × 109 pfu	m-MIF antisense	BCG-LPS liver failure, mice, IV	↑Survival
Oe et al[45], 2004	7 × 108 pfu	h-VEGF + or r-HGF (CAG)	DMN cirrhosis 70% PH, rats, IV	↑SECs and hepatocytes proliferation
Oe et al[82], 2005	7 × 108 pfu	r-HGF, or h-VEGF (CAG)	AAF/70% PH, rats, IV	↑Oval cell proliferation, ↑regeneration
Wullaert et al[84], 2005	2.5 × 109 pfu	m-ABIN-1 (CMV)	TNF + Gal-liver injury, mice, IV	↑Survival, ↓apoptosis,
Ichiba et al[94], 2005	1 × 109 pfu	r-TPO (CAG)	AAF/70% PH, rats, IV	↑Oval cell proliferation
Khai et al[44], 2006	1 × 1011 vp	h-HB-EGF or h-HGF (RSV)	Fas-induced injury, mice, IV	↓Apoptosis and ↑proliferation by both
Ozawa et al[47], 2006	5 × 108 pfu each	r-HGF, +/or h-TGFβ2R (CAG)	DMN cirrhosis 10% PH, rats, PV	↑Proliferation, ↑survival, ↓cirrhosis
Tan et al[96], 2006	1 × 1011 vp	m-HNF6 (CMV)	70% PH, mice, IV	↑Proliferation
Yuasa et al[85], 2007	1 × 109 pfu	r-HGF, (CBA)	85% PH, rats, IV	↓Apoptosis, ↑proliferation, ↑survival
Ueno et al[83], 2007	5 × 108 pfu	r-HGF (CAG)	DMN cirrhosis 70% PH, rats, sPV	↑Proliferation, ↑survival, ↓cirrhosis
Atta et al[93], 2009	7 × 109 pfu	h-HGF, h-VEGF (CMV)	Healthy, dogs, IV	↑SEC and hepatocytes proliferation
Naked plasmid DNA
Yang et al[90], 2001	10-40 μg/wk × 8	h-HGF (CMV)	Healthy, mice, IV	↑Proliferation
Xue et al[89], 2003	50 μg × 3	r-HGF	CCl4 cirrhosis 70% PH, mice, IM + EP	↑Proliferation
Zhang et al[91], 2005	200 μg/kg per 12 h × 4	r-ALR	CCl4 liver injury, rats, IV, IP	↓ALT and AST, ↑proliferation, ↑survival
Horiguchi et al[86], 2009	-	h-HGF	DMN cirrhosis, dogs, IA	↓ALT and AST, ↓fibrosis, ↑survival
HVJ Liposomes
Ueki et al[88], 1999	20 or 40 mg weekly × 4	h-HGF (SRa)	DMN cirrhosis, rats, IM	↓Apoptosis, ↑survival, ↑r-HGF, ↓fibrosis
Ogushi et al[92], 2003	50 nmol	NF-κB decoy ODN	P. acnes-LPS liver injury, mice, PV	↑Survival, ↑proliferation, ↓apoptosis
Nishino et al[87], 2008	20 μg	h-HGF (SRα)	DMN cirrhosis 70% PH, rats, PV	↑Proliferation, ↑survival, ↓apoptosis
Takahashi et al[50], 2009	50 nmol	NF-κB decoy ODN	90% PH, mice, PV	↑Survival, ↓apoptosis

AAF: Acetylaminofluorene; ALT: Alanine transaminase; AST: Aspartate transaminase; ABIN-1: A20 binding inhibitor of nuclear factor κB; ALR: Augmenter of liver regeneration; BCG: Bacille Calmette-Guerin; CAG: Chicken β-actin promoter and cytomegalovirus enhancer; CBA: Chicken β-actin; D-Gal: D-galactosamine; TNF: Tumor necrosis factor; HVJ: Hemagglutinating virus of Japan; DMN: Dimethylnitrosamine; EP: Electroporation; Gal: Galactosamine; h: Human; h-HIL-6: Human hyper-interleukin-6 (IL-6) cDNA gene coding the human sIL-6R (amino acid residues 1-323) and human IL-6 (amino acid residues 29-212) fused by a synthetic DNA linker; HNF6: Hepatocyte nuclear factor 6; IA: Intra-arterial injection (hepatic artery); IM: Intramuscular injection; IP: Intraperitoneal injection; IV: Intravenous injection; M: Murine; HGF: Hepatocyte growth factor; MIF: Macrophage migration inhibitory factor; MIP-2: Macrophage inflammatory protein-2; VEGF: Vascular endothelial growth factor; CMV: Cytomegalovirus; ODN: Oligodeoxynucleotides; PH: Partial hepatectomy; LPS: Lipopolysaccharide; SECs: Sinusoidal endothelial cells; P. acnes: Propionibacterium acnes; PV: Portal vein injection; r: Rat; sPV: Selective portal vein injection; SRα: Simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat; TAA: Thioacetamide; TGFβ2R: Truncated transforming growth factor β type 2 receptor; TPO: Thrombopoietin; TU: Transducing units (1 vp = 25 TU); vp: Viral particles (1 vp = 100 pfu).