Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

Figures & data

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.

Figure 1. Viral and non-viral vectors for the treatment of renal fibrosis in vivo.

Table 2. Islet cell transplantation using viral and non-viral vectors for the treatment of diabetes mellitus.

Vectors		Moderated substance	Administration route	Transplanted site	Effects	Authors (year published)	Reference No.
Viral vectors	Adenovirus	GLP-1	Direct transplantation	Left kidney capsule	Enhanced islet cell survival. Preserved islet mass. Achieved normoglycemia	Chae et al. (2012)	[54]
Non-viral vectors	PEG	Urokinase	Portal vein injection	Liver	Increased plasma insulin level. Inhibited IBMIR	Teramura and Iwata (2011)	[80]
	PEG	sCR1, heparin	Portal vein injection	Liver	Increased plasma insulin level. Normalized glucose level. Reduced islet cell damage by IBMIR	Teramura et al. (2013)	[81]
	PGA	None (only polymer layer)	Direct transplantation	Abdominal subcutaneous tissue	Normalized blood glucose level. Revascularized transplanted islet cells	Juang et al. (1996)	[82]
	PET mesh bag	bFGF	Direct transplantation	Intermuscular space	Normalized blood glucose level	Balamurugan et al. (1996)	[83]
	PET mesh bag	Agarose	Unknown	Peritoneal cavities	Induced blood vessels around transplanted islets	Gu et al. (2000)	[84]
	PET mesh bag	Agarose	Unknown	Peritoneal cavities	Induced prevascularization. Maintained normoglycemia over the long term	Gu et al. (2000)	[85]
	PET mesh bag coated with PVA	bFGF in agarose and hyaluronic acid	Direct transplantation	Subcutaneous tissue of dorsum	Induced angiogenesis. Normalized blood glucose levels in the long term	Kawakami et al. (2001)	[86]
	Cationic lipid reagent	VEGF	Direct transplantation	Left kidney capsule	Normalized blood glucose level. Preserved transplanted islet cells with increasing vascularization	Chae et al. (2005)	[43]
	R3V6 peptide micelles	siRNA-iNOS, 17b-estradiol	Direct transplantation	Left kidney capsule	Improved glycemic control. Reduced apoptosis of transplanted islet cells	Hwang et al. (2015)	[87]
	Magnetic iron oxide nanoparticles	siRNA-human caspase-3	Direct transplantation	Left kidney capsule	Decreased apoptosis in transplanted islet cells	Wang et al. (2011)	[88]
	Magnetic iron oxide nanoparticles	siRNA-β2 microglobulin	Direct transplantation	Left kidney capsule	Delayed onset of diabetes mellitus caused by immune rejection	Wang et al. (2012)	[89]

Abbreviations: GLP-1: glucagon-like peptide-1; IBMIR: instant blood-mediated inflammatory reactions; PEG: polyethylene glycol; PGA: polyglycolic acid; PET: polyethylene terephthalate; bFGF: basic fibroblast growth factor; CR1: soluble complement receptor 1; PVA: polyvinyl alcohol hydrogel; VEGF: vascular endothelial growth factor; R3V6: three arginine and six valine; siRNA: short interfering RNA; iNOS: inducible nitric oxide synthase.

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