Table 2 Mechanism-based therapeutic strategies for collagen-related disease
COL4A1, COL4A2, COL4A5Col4a1 disease and ASER retained protein, ER stress pathwayChemical chaperones, e.g. 4-phenylbutyrate (4PBA) to reduce ER stress and increase secretion of correctly folded protein[58,61,68,71]
COL4A5ASBlood pressure by targeting renin–angiotensin systemAngiotensin-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-21HMG-CoA-reductase inhibitor (cerivastatin)[116]
Vasopeptidase inhibitor AVE7688[117]
Anti-miR-21 oligonucleotides[118]
Oxidative stress, inflammation and fibrosis: Nrf2Nrf2 activator, e.g. bardoxolone methyl (BARD)*[119]
STAT3 signallingSTAT3 inhibitor, e.g. stattic[59]
Functional correctionGene therapy: restoration of network proof of concept[120]
Cell therapy
Bone marrow-derived stem cells
Amniotic fluid stem cells[122]
COL6A1Bethlem myopathy, Ullrich congenital muscular dystrophyReactivation of autophagymTOR inhibitor, e.g. Rapamycin[82]
Low protein diet*[123]
Mitochondrial defect: opening of Mitochondrial permeability transition pore (mPTP)Cyclosporin A Cyclophilin inhibitor, e.g. NIM811, Debio25 (alisporivir)*[125,83,37,126,127]
Metabolic defectsAdiponectin[128]
Functional correction Collagen VI-producing cellsCell therapy: fibroblast grafting[81]
Adipose-derived stem cell transplant[129]
Dominant negative mutationGene silencing with AONs or siRNAs[130,131,132,133]
Splice mutationsAON-mediated exon skipping[134]
COL7A1DEBWound healingInjecting 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 correctionExon skipping[140]
RDEBFunctional correctionEx 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-βAngiotensin II type 1 receptor antagonist: losartan[148]
DDEBFunctional correctionAllele-specific silencing via siRNA[149]
Gene editing using NHEJ to knockout mutant allele[146,150]
Deficient collagen VII levels in ECMProtein replacement therapy[151,152]
COL15A1/COL18A1Muscular defectMitochondrial defect (opening permeability transition pore) and ROS productionCyclosporine A Angiotensin II type 1 receptor antagonist, e.g. losartan[44]
  • Clinical trials are indicated by *. Abbreviation: AON, antisense oligonucleotide.