Table 1.

Gene therapies with viral and non-viral vectors for the treatment of diabetes mellitus.

Vectors		Transgene	Target organ	Administration route	Effects	Authors (year published)	Reference No.
Viral vectors	Adenovirus	PDX-1-DNA	Pancreas	Common bile duct	Neogenesis and ductal proliferation of pancreatic β cells	Taniguchi et al. (2003)	[10]
	Adenovirus	ISL-1-DNA	Pancreas	Common bile duct	Promoted regenerative potential of pancreatic cells	Miyazaki et al. (2012)	[11]
	Adenovirus	NEUROG3-DNA	Pancreas	Tail vein injection	Delayed the development of diabetes mellitus	Phillips and Kay (2014)	[12]
	Adenovirus	GLP-1(7–37)-DNA	Intestines	Tail vein injection	Increased plasma GLP-1 level. Normoglycemia	Lee et al. (2008)	[13]
	Adenovirus	GLP-1(7–37)-DNA	Intestines	Tail vein injection	Increased plasma GLP-1 level. Decreased blood glucose level	Parsons et al. (2007)	[14]
	Recombinant adenovirus	GLP-1-DNA	Intestines	Tail vein injection	Increased plasma GLP-1 level. Increased insulin secretion, sensitivity, and tolerance. Increased insulin receptor substrate in the liver. Increased pancreatic β cell function. Increased insulin-stimulated glucose uptake in adipocytes. Decreased blood glucose level	Lee et al. (2007)	[15]
	Double-stranded AAV	GLP-1(7–37)-DNA	Intestines	Portal vein injection	Increased plasma GLP-1 level. Increased insulin secretion and β cell mass. Decreased blood glucose level	Choi and Lee (2011)	[16]
	Double-stranded AAV-8	GLP-1-DNA	Intestines	Tail vein injection	Increased plasma GLP-1 level. Decreased blood glucose level. Improved glucose tolerance	Liu et al. (2007)	[17]
	Recombinant adenovirus	GLP-1(7–37)-DNA	Intestines	Intra-intestinal injection	Increased plasma insulin and GLP-1 levels. Decreased blood glucose level	Lee et al. (2007)	[15]
	Double-stranded AAV	GLP-1 and HGF/NK1-DNA	Intestines	Intraperitoneal injection	Delayed onset of diabetes mellitus. Increased pancreatic β cell mass and insulin secretion	Gaddy et al. (2010)	[18]
	Double-stranded AAV-8	GLP-1-DNA	Intestines	Intraperitoneal injection	Increased serum GLP-1 expression. Protected against the development of diabetes mellitus	Riedel et al. (2010)	[19]
	Double-stranded AAV-8	GLP-1 and IL-4-DNA	Intestines	Intraperitoneal injection	Increased β cell mass and prevented β cell apoptosis. Decreased blood glucose level	Gaddy et al. (2012)	[20]
	AAV-9	GLP-1 and REG3 protein	Intestines	Intraperitoneal injection	Prevented hyperglycemia. Increased insulin-positive cell mass	Tonne et al. (2013)	[21]
	AAV-8	IL-2	Pancreas	Intraperitoneal injection	Prevented onset of diabetes	Flores et al. (2014)	[22]
	AAV-2	Klotho	Pancreas	Intraperitoneal injection	Improved glucose tolerance and attenuated β cell apoptosis.	Lin and Sun (2015)	[23]
					Enhanced insulin storage in β cells and increased plasma insulin levels
Non-viral vectors	PEI	AFT3-siRNA	Pancreas	Tail vein injection	Attenuated ER stress-mediated pancreatic β cell dysfunction	Kim et al. (2013)	[24]
	PEI	Fas-siRNA	Pancreas	Tail vein injection	Delayed the development of diabetes mellitus	Jeong et al. (2010)	[25]
	PEI	GLP-1(7–37)-plasmid DNA	Intestines	Tail vein injection	Increased insulin secretion. Decreased blood glucose level	Choi et al. (2005)	[26]
	Cationic nanomicelles comprising chitosan	IL-4 and IL-10-plasmid DNA	Whole body	Intra-muscle injection	Increased plasma IL-4 and IL-10 expression levels. Decreased blood glucose level	Mandke and Singh (2012)	[27]
	Cationic nanomicelles comprising chitosan	GLP-1-plasmid DNA	Intestines	Subcutaneous injection in dorsal or intramuscular injection in hind legs	Enhanced insulin secretion. Improved glucose tolerance	Jean et al. (2011)	[28]
	ABP	Exendin-4 plasmid DNA	Whole body	Intravenous injection	Decreased blood glucose level	Kim et al. (2012)	[29]
	Ultrasound-targeted microbubble	ANGPTL8 plasmid DNA	Whole body	Intravenous injection	Promoted the proliferation of aged β cells and expanded the β cell mass. Improved glucose tolerance and increased the fasting blood insulin level	Chen et al. (2006)	[30]

Abbreviations: PDX-1: pancreas/duodenum homeobox protein 1; ISL-1: insulin gene enhancer protein-1; GLP-1: glucagon-like peptide-1; DNA: deoxyribonucleic acid; AAV: adeno-associated viral vector; HGF/NK1: N and K1 domains of hepatocyte growth factor; REG3: regenerating islet-derived protein 3; IL-2: interleukin-2; PEI: polyethylenimine; ATR3: activating transcription factor 3; ER: endoplasmic reticulum; IL-4: interleukin-4; IL-10: interleukin-10; ABP: arginine-grafted bioreducible polymer; ANGPTL8: angiopoietin-like protein 8.