Abstract
Fibrosis results from the excessive accumulation of extracellular matrix in chronically injured tissue. The fibrotic process is governed by crosstalk between many signaling pathways. The search for an effective treatment is further complicated by the fact that there is a degree of tissue-specificity in the pathways involved, although the process is not completely understood for all tissues. A plethora of drugs have shown promise in pre-clinical models, which is not always borne out translationally in clinical trial. With the recent approvals of two antisense oligonucleotides for the treatment of the genetic diseases Duchenne muscular dystrophy and spinal muscular atrophy, we explore here the potential of antisense oligonucleotides to knockdown the expression of pro-fibrotic proteins. We give an overview of the generalized fibrotic process, concentrating on key players and highlight where antisense oligonucleotides have been used effectively in cellular and animal models of different fibrotic conditions. Consideration is given to the advantages antisense oligonucleotides would have as an anti-fibrotic therapy alongside factors that would need to be addressed to improve efficacy. A prospective outlook for the development of antisense oligonucleotides to target fibrosis is outlined.
Highlights
IntroductionWhen a tissue is injured acutely, the pathological response results in wound healing
One approach that has shown much preclinical promise is the use of antisense oligonucleotides (AOs) to suppress expression of pro-fibrotic factors
AOs themselves have been utilized to target TGFβ signaling at multiple points, including components of the TGFβ signaling cascade, such as ALK5 and SMAD3, and modulators of TGFβ signaling, such as connexin43 and micro RNAs (miRs), for the amelioration of pathological fibrogenesis
Summary
When a tissue is injured acutely, the pathological response results in wound healing The inflammation response is acutely amplified by the release of chemokines, such as interleukin-13 and interleukin-4, and the release of cytokines, such as transforming growth factor beta 1 (TGFβ1) and platelet-derived growth factor (PDGF), by the recruited immune cells themselves This in turn leads to the temporary activation and proliferation of myofibroblasts to repair the insult. Several beneficial features of AOs make this strategy attractive, such as their non-immunogenicity, the transience of target knockdown, the potential for flexibility in dosage, as well as the recent approval of two antisense oligonucleotide drugs for the treatment of genetic disease [8] On this basis, this review will focus on the use of AOs as anti-fibrotic agents
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