Table 2.

Mechanism-based therapeutic strategies for collagen-related disease

Gene	Disease	Mechanism-target	Treatment	References
COL4A1, COL4A2, COL4A5	Col4a1 disease and AS	ER retained protein, ER stress pathway	Chemical chaperones, e.g. 4-phenylbutyrate (4PBA) to reduce ER stress and increase secretion of correctly folded protein	[58,61,68,71]
COL4A5	AS	Blood pressure by targeting renin–angiotensin system	Angiotensin-converting enzyme inhibitors, e.g. ramipril	* [114]
			Angiotensin II type 1 receptor blockers, e.g. losartan	*[115]
		Fibrosis-Transforming growth factor-β 1 (TGF-β), Connective tissue growth factor, miR-21	HMG-CoA-reductase inhibitor (cerivastatin)	[116]
			Vasopeptidase inhibitor AVE7688	[117]
			Anti-miR-21 oligonucleotides	[118]
		Oxidative stress, inflammation and fibrosis: Nrf2	Nrf2 activator, e.g. bardoxolone methyl (BARD)	*[119]
		STAT3 signalling	STAT3 inhibitor, e.g. stattic	[59]
		Functional correction	Gene therapy: restoration of network proof of concept	[120]
			Cell therapy Bone marrow-derived stem cells	[121]
			Amniotic fluid stem cells	[122]
COL6A1	Bethlem myopathy, Ullrich congenital muscular dystrophy	Reactivation of autophagy	mTOR inhibitor, e.g. Rapamycin	[82]
			Low protein diet	*[123]
			Spermidine	[124]
		Mitochondrial defect: opening of Mitochondrial permeability transition pore (mPTP)	Cyclosporin A Cyclophilin inhibitor, e.g. NIM811, Debio25 (alisporivir)	*[125,83,37,126,127]
		Metabolic defects	Adiponectin	[128]
		Functional correction Collagen VI-producing cells	Cell therapy: fibroblast grafting	[81]
			Adipose-derived stem cell transplant	[129]
		Dominant negative mutation	Gene silencing with AONs or siRNAs	[130,131,132,133]
		Splice mutations	AON-mediated exon skipping	[134]
COL7A1	DEB	Wound healing	Injecting fibroblast cells	*[135]
			Grafting revertant mosaicism skin-keratinocytes	*[136]
			Genome editing patient-derived IPSC cells and transplant	[137]
			Mesenchymal stromal cell therapy transplant	*[138]
			Human placental‐derived stem cell transplant	[139]
		Functional correction	Exon skipping	[140]
	RDEB	Functional correction	Ex vivo TALEN gene editing	[141]
			Ex vivo CRISPR Genome editing keratinocytes	*[142]
			RNA trans-splicing	[143]
			Polymer-mediated cDNA delivery	[144]
			Ex vivo retroviral transduction	[145]
			AON-mediated exon skipping	[146]
			Read through of Premature termination codons (PTCs)	See review [147]
		Fibrosis: TGF-β	Angiotensin II type 1 receptor antagonist: losartan	[148]
	DDEB	Functional correction	Allele-specific silencing via siRNA	[149]
			Gene editing using NHEJ to knockout mutant allele	[146,150]
		Deficient collagen VII levels in ECM	Protein replacement therapy	[151,152]
COL15A1/COL18A1	Muscular defect	Mitochondrial defect (opening permeability transition pore) and ROS production	Cyclosporine A Angiotensin II type 1 receptor antagonist, e.g. losartan	[44]

Clinical trials are indicated by *. Abbreviation: AON, antisense oligonucleotide.