Internal ribosome entry site-based vectors for combined gene therapy

Table 1 Preclinical studies of combined gene therapy with co-administration of monocistronic vectors

Pathology	Therapeutic genes	Animal model	Vector type	Ref.
Cancers
Leukemia, melanoma	Angiostatin + endostatin	Mouse	Retrovirus	Scappaticci et al[4], 2001
Ovarian cancer	Angiostatin + endostatin	Mouse	AAV	Ponnazhagan et al[3], 2004
Glioblastoma	VEGF-R1 + angio-endo (Statin AE)	Mouse	SB transposon	Ohlfest et al[60], 2005
Pancreatic cancer	TSP1 + endostatin	Mouse	AAV	Zhang et al[61], 2007
Cardiovascular diseases
Limb ischemia	VEGFA + angiopoietin-1	Rabbit	Plasmid	Chae et al[5], 2000
Limb ischemia	VEGFA + FGF2	Mouse	Plasmid	Lee et al[59], 2007
Limb ischemia	VEGFA + PDGFB	Rabbit	AAV	Kupatt et al[58], 2010
Heart ischemia	VEGFA + PDGFB	Pig	AAV	Kupatt et al[58], 2010
Rear diseases
DMD	Microdystrophin + IGF1	Mouse	AAV	Abmayr et al[62], 2005

DMD: Duchenne muscular dystrophy; VEGF: Vascular endothelial growth factor; FGF2: Fibroblast growth factor 2; AAV: Adeno-associated virus.

Table 2 Preclinical studies of combined gene therapy using multicistronic vectors

Pathology	Therapeutic genes	Animal model	IRES	Vector type	Ref.
Cancers
Fibrosarcoma	CD70 + CD80	Mouse	EMCV	Retrovirus	Couderc et al[2], 1998
Melanoma	Angio-endo fusion	Mouse	None (fusion)	Retrovirus	Scappaticci et al[79], 2001
Multiple myeloma	IL12 subunits + CD80	Mouse	EMCV + FMDV	Retrovirus	Wen et al[69], 2001; Li et al[67], 2003
Melanoma	CD70 + CD80	Mouse	EMCV, c-myc, FGF2, HTLV1	Retrovirus	Douin et al[63], 2004
Ovarian cancer	Angiostatin + endostatin	Mouse	EMCV	AAV	Isayeva et al[66], 2005
Head and neck cancer	Angio-endo fusion	Mouse	None (fusion)	Vaccinia virus	Tysome et al[80], 2011
Pancreas cancer	CXCL4L1 + fibstatin	Mouse	FGF1	AAV, Lentivector	Prats et al[68], 2013
Cardiovascular diseases
Limb ischemia	FGF2 + Cyr 61	Mouse	FGF1	Plasmid	Rayssac et al[10], 2009
Limb ischemia	VEGFA + BMP7	Rabbit	EMCV	AAV	Zhang et al[65], 2010
Limb ischemia	VEGFA + FGF4	Mouse	EMCV	AAV	Jazwa et al[64], 2013
Heart ischemia	Gata4 + Mef2C + Tbx5	Rat	None (2A element)	Lentivector	Mathison et al[75], 2014
Neurodegenerative diseases
Parkinson	TH + AADC + CH1	Rat	EMCV	Lentivector	Azzouz et al[73], 2002
					Stewart et al[74], 2011
AMD	Angiostatin + endostatin	Mouse	EMCV	Lentivector	Kachi et al[70], 2009

BMP7: Bone morphogenetic protein 7; Gata4: GATA binding protein 4; Mef2C: Myocyte-specific enhancer factor 2C; Tbx5: T-box transcription factor 5; TH: Tyrosine hydroxylase; AADC: aromatic L-amino acid decarboxylase; CH1: GTP cyclohydrolase-1; AMD: Age-related macular degeneration.

Table 3 Clinical studies of combined gene therapy

Pathology	Therapeutic genes	IRES	Vector type	Outcome	Ref.
Ischemic heart disease	VEGFA + FGF2	EMCV	Plasmid	Moderate benefits	Kukula et al[90], 2011
Parkinson	TH + AADC + CH1	EMCV	Lentivector	Benefits for 15/15 patients	Palfi et al[91], 2014
Mucopolysaccharidosis type IIIA	SGSH + SUMF1	EMCV	Lentivector	Benefits for 1/4 patients, stabilization for 3/4	Tardieu et al[71], 2014

TH: Tyrosine hydroxylase; AADC: Aromatic L-amino acid decarboxylase; CH1: GTP cyclohydrolase-1; SGSH: N-sulfoglycosamine sulfohydrolase; SUMF1: Sulfatase-modifying factor.