MicroRNA mimicry blocks pulmonary fibrosis

Abstract

Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR-29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast-enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR-29 levels in vivo for several days. Moreover, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…miR-133, and the more ubiquitous miR-29 and miR-30 (17). In dystrophic muscles, the absence of dystrophin disrupts such circuitry, leading to reduced levels of specific miRNAs, which favors the onset of dystrophic pathogenic traits such as oxidative damage through upregulation of the miR-1 target glucose-6-phosphate dehydrogenase (G6PD) and fibrosis through deregulation of the collagen mRNAs targeted by miR-29 (17,24,25) (Figure 1). Notably, both miR-1 and miR-29, which are poorly expressed in murine and human dystrophic muscles, were recovered in exon skipping-treated mdx mice (a murine model of DMD) and DMD myoblasts (17).…”

Function and Therapeutic Potential of Noncoding RNAs in Cardiac Fibrosis

“…Although the therapeutic increase of a miRNA still requires optimization, upregulation of miR-29 levels by either miR-29 mimics or viral delivery has already proven to have therapeutic potential in several fibrotic diseases, like kidney, [24][25][26] liver, 27-29 lung, 30,31 and systemic sclerosis. 32 The miR-15 family consists of 6 evolutionarily conserved miRNAs (miR-15a, miR-15b, miR-16, miR-195, miR-497, and miR-322), which are abundantly expressed in several cardiac cell types.…”

“…Moreover, therapeutic delivery of these miR-29 mimics in a mouse model of pulmonary fibrosis was able to decrease collagen expression and block and even reverse pulmonary fibrosis. 31 Although both miR-21 and miR-29 were initially studied for their involvement in cardiac fibrosis, the fact that they are currently being pursued for indications in other tissues likely reflects the targeting efficiency of the heart. Systemic delivery of miRNA therapeutics does lead to cardiac targeting, but with a lower efficiency than other tissues, like liver, kidney, and lung.…”

MicroRNA-29 Family Suppresses Mineralization in Dental Follicle Cells

“…We found that transfection with a combination of miR-29a, -29b and -29c mimics suppressed collagen type I production in hDFC. When miR-29b mimic was transfected into a mouse fibroblast cell line (NIH 3T3), a dose-dependent decrease in col1a1 expression was observed 20) . It has also been reported that miR-29b is the most effective suppressor of collagen type I at the mRNA and protein level via its direct binding to col1a1 3'-UTR in human stellate cells, which are involved in liver fibrogenesis 21) .…”