MicroRNA: Potential biomarkers and therapeutic targets for allergic asthma?

Figures & data

Figure 1. Targeting miRNAs with therapeutic molecules. (A) Chemically modified AONs with a sequence complementary to the miRNA of interest. Antagomirs are 3’ cholesterol conjugated, 2’-O-Me-modified oligonucleotides with terminal phosphorothioate linkages for increased cellular uptake and stability in vivo. LNA/DNA mixmers are AONs that inhibit miRNA function by targeting the 5’ region of the miRNA. (B) Liposomes are vesicles with a lipid bilayer that are used to deliver miRNA mimics in vivo. Liposomes can be coated with polyethylene glycol (PEG) to reduce recognition by macrophages. Monoclonal antibodies can be covalently coupled to liposomes for targeted delivery.

Table I. In vivo administration of miRNA therapeutics.

Targeted miRNA	Disease model	Route of administration	Disease outcome	Ref.
Let-7a	Breast cancer	Intravenous	Suppression of tumor growth	(75)
miR-122	Metabolic disease	Intravenous	Reduction of plasma cholesterol	(65)
miR-122	Hepatitis C virus	Intravenous	Suppression of HCV viremia	(69)
miR-126	Allergic airway disease	Intranasal	Suppression of airway hyper-responsiveness	(42)
miR-199b	Heart failure	Intraperitoneal	Inhibition of heart hypertrophy and fibrosis	(76)
miR-145	Allergic airway disease	Intranasal	Suppression of airway hyper-responsiveness	(46)
miR-145	Glioblastoma	Intracranial	Suppression of tumorigenesis	(77)
miR-21	Autoimmune	Intraperitoneal	Suppression of splenomegaly	(78)
miR-33	Atherosclerosis	Subcutaneous	Reduction of atherosclerosis	(79)
miR-34a	Multiple myeloma	Intratumoral	Inhibition of tumor growth	(80)

Table II. Companies developing miRNA-related therapies.

Company	Diseases	Target miRNAs	Product pipeline
Santaris Pharma A/S	Hepatitis C	miR-122	Phase II
MiRNA Therapeutics	Oncology	miR-34	Phase I
	Oncology	let-7	Preclinical
	Oncology	miR-16	Preclinical
miRagen Therapeutics	Heart failure	miR-208	Preclinical
	Post-myocardial infarction remodeling	miR-15/195	Preclinical
	Vascular disease	miR-145	Preclinical
	Fibrosis	miR-29	Preclinical
	Cardiometabolic	miR-208	Preclinical
Regulus Therapeutics	Hepatitis C	miR-122	Phase I
	Glioblastoma	miR-10b	Preclinical
	Hepatocellular carcinoma	miR-21	Preclinical
	Kidney fibrosis	miR-22	Preclinical
	Atherosclerosis	miR-33	Preclinical

Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21: 185–91.

 PubMed Web of Science ®Google Scholar

Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98.

 PubMed Web of Science ®Google Scholar

Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327:198–201.

 PubMed Web of Science ®Google Scholar

Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc Natl Acad Sci U S A. 2009;106:18704–9.

 PubMed Web of Science ®Google Scholar

da Costa Martins PA, Salic K, Gladka MM, Armand AS, Leptidis S, el Azzouzi H, et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol. 2010;12:1220–7.

 PubMed Web of Science ®Google Scholar

Collison A, Mattes J, Plank M, Foster PS. Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. J Allergy Clin Immunol. 2011;128:160–7 e4.

 PubMed Web of Science ®Google Scholar

Speranza MC, Frattini V, Pisati F, Kapetis D, Porrati P, Eoli M, et al. NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget. 2012;3:723–34.

 Google Scholar

Garchow BG, Bartulos Encinas O, Leung YT, Tsao PY, Eisenberg RA, Caricchio R, et al. Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med. 2011;3: 605–15.

 PubMed Web of Science ®Google Scholar

Rotllan N, Ramirez CM, Aryal B, Esau CC, Fernandez-Hernando C. Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice—brief report. Arterioscler Thromb Vasc Biol. 2013;33:1973–7.

 PubMed Web of Science ®Google Scholar

Di Martino MT, Leone E, Amodio N, Foresta U, Lionetti M, Pitari MR, et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res. 2012;18:6260–70.

 PubMed Web of Science ®Google Scholar