Adeno-associated viral (AAV) vector-mediated therapeutics for diabetic cardiomyopathy – current and future perspectives

Figure 1. Overview of dysregulated major signalling pathways dysregulated in diabetic cardiomyopathy Diabetes-induced molecular impairments lead to cardiac remodelling, inflammation, oxidative stress and impaired calcium handling, contributing to cardiac dysfunction that initially develops as diastolic dysfunction. Over time, impairment of endothelial and smooth muscle cells in the vasculature can lead to reduced coronary microvascular blood flow, as a result of this microvascular dysfunction. The dysfunction in the vasculature and the myocardium can eventually lead to LV systolic dysfunction; Akt, protein kinase B; CTGF, connective tissue growth factor; eNOS, endothelial nitric oxide synthase; HBP, hexosamine biosynthesis pathway; LV, left ventricular; NFκB, nuclear factor-κB; Nox, NADPH oxidase; PI3K, phosphoinositide-3 kinase; PKC, protein kinase-C; PLN, phospholamban; ROS, reactive oxygen species; SERCA2a, sarcoplasmic/endoplasmic reticulum ATPase- Ca2+; TGF-β, transforming growth factor-β; TNFα, tumour necrosis factor-α (see text for references).

Figure 2. Principles of AAV-mediated gene therapy Adeno-associated virus (AAV) binds to the host glycosylated cell surface receptor to trigger clathrin-mediated endocytosis internalization. The AAV then moves through the cytosol via the cytoskeletal network. Conformational changes are then triggered by pH changes in the cellular environment, leading to endosomal release. The AAV undergoes transport to the nucleus, releasing its cargo, where it is then transcribed into double-stranded DNA for transcription, or undergoes integration to the host genome (which rarely occurs). Messenger RNA produced from transcription of the cargo leads to its translation to the protein-of-interest outside of the nucleus. Production of this protein-of-interest then enables the cardioprotective effects that are observed in response to AAV-mediated gene therapy.

Figure 3. Outline of reported AAV-based potential therapeutics for diabetic cardiomyopathy Current AAV gene therapies reported to date to target multiple signalling pathways and molecules in cardiac tissue proposed for the treatment of diabetic cardiomyopathy. ADP, adenosine diphosphate; βARKct; β-adrenergic receptor kinase 1 (carboxy terminus); BPIFB4, bactericidal/permeability-increasing fold-containing family B member 4; CRH2, corticotrophin-releasing hormone receptor-2; CTRP, C1q/tumour necrosis factor-related protein; dADP, deoxyadenosine diphosphate; dATP, 2-deoxyadenosine triphosphate; FGF, fibroblast growth factor-2; GRK2; G protein-coupled receptor kinase-2; HO-1, heme oxygenase-1; I-1c, constitutively active inhibitor-1; miRNA, micro RNA; NGF, nerve growth factor; OGA, O-GlcNAc-ase; OGT, O-GlcNAc-transferase; PI3K(p110α), phosphoinositide 3- kinase (p110α); PIM-1, pro-viral integration site for Moloney murine leukaemia virus; PP1, protein phosphatase-1; RNR, ribonucleotide reductase; Ryr2, ryanodine receptor-2; S100A1, S100 calcium-binding protein A1; SDF-1, stromal-derived factor-1; SOD, superoxide dismutase; Sp-1; specificity protein-1; sTGFβ2, soluble transforming growth…