Gene and miRNA based therapies in cardiovascular and renal disease: Spanning discovery science
to clinical translation.
Andrew H Baker, BHF Professor of Translational Cardiovascular Sciences, University of Glasgow
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre,
University of Glasgow, UK
Our laboratory is interested in understanding the basic mechanisms that underpin pathological tissue
remodeling, with a focus on acute injury; including vascular remodeling following vein grafting, stent
deployment, pulmonary vascular remodelling and renal fibrosis. Further, we are focused on strategies to
prevent these pathological events using gene and miRNA-based therapies. I will use examples of each to
illustrate these findings and discuss strategies to translate to the clinic.
Patency rates for coronary artery bypass grafting (CABG) procedures using autologous saphenous vein
(SV) remain poor. The vast majority of failures are due to neointima formation and superimposed
atherosclerosis. Since many of the molecular and cellular mechanisms that lead to neointima formation
have been identified, a number of strategies have emerged. These include modulation of smooth muscle
cell migration, proliferation and/or apoptosis. Vein grafting is highly suited for human gene therapy since it
allows ex vivo manipulation of the vein prior to grafting into the coronary circulation of the patient. Our
research has shown that overexpression of certain genes, including TIMP-3, p53 and NogoB has a
beneficial effect by reducing neointima formation. Clinical translation is ongoing.
MicroRNAs (miRNAs) are short non-coding RNAs, which post-transcriptionally regulate gene expression. In
consideration of the role played by miRNAs in cell proliferation and vascular remodeling, we evaluated the
involvement of the smooth muscle cell-associated miRNAs miR-143 and miR-145 in the development of
pulmonary arterial hypertension. Significant dysregulation of these miRNAs in PAH has been observed in
animal models and in pathological samples and knockout or knockdown has been shown to be therapeutic.
Manipulation of miR-145 may therefore represent a novel strategy to prevent the development of PAH.
Chronic kidney disease (CKD) is associated with substantial medical and socioeconomic burden. Renal
fibrosis results from accumulation of extracellular matrix proteins with replacement of normal tissue by scar.
We have shown previously that miRNA (miR)-214 is upregulated in preclinical models of renal injury. MiR214-/- mice had significantly attenuated interstitial fibrosis compared to wild-type. Pro-fibrotic gene
expression was also decreased. This anti-fibrotic effect was phenocopied in C57bl/6 mice administered
subcutaneously with anti-miR-214 who underwent UUO compared to animals who received control anti-miR
(86% reduction vs control anti-miR treated animals, p<0.001).
Surprisingly, despite previously
demonstrating the regulation of miR-214 and miR-21 was regulated by TGF-β; in vivo the endogenous
levels were not sensitive to inhibition of canonical transforming growth factor-β (TGF-β) signalling. These
studies demonstrate that miR-214 activation in renal injury promotes fibrosis independent of TGF-β
signalling in vivo and that antagonism of miR-214 may represent a novel anti-fibrotic treatment in the kidney.
Collectively, these studies highlight the translational potential of gene and miRNA-based approaches as
novel therapies in pathological cardiovascular tissue remodeling events.