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Publication Number
US-8691783-B2
Publication Date
2014-04-08
Expiration Date
Abstract
The present invention relates to a modulator, in particular an inhibitor, of microRNA-24 (miR-24) and to direct and indirect miR-24 targets for use in a method of treatment and/or prevention of ischemia, in a method of prevention of endothelial apoptosis or in a method of induction of angiogenesis. The present invention further relates to a precursor of miR-24 and to siRNAs or shRNAs against direct or indirect miR-24 targets for use in a method of treatment of angiogenesis associated with cancer. The present invention also relates to an in vitro method for diagnosing ischemia or prevalence or disposition for ischemia, and to a method for identifying a modulator of miR-24 and/or direct or indirect miR-24 targets. In addition, the present invention relates to pharmaceutical compositions or kits comprising any of the above agents, to endothelial cells devoid of expressing functional miR-24, and to a non-human, transgenic animal comprising these endothelial cells.
Core Innovation
The patent describes an miR-24-centered therapeutic and diagnostic framework in which a method administers an inhibitor of microRNA-24 (miR-24) to a subject in need of treatment or induction. The inhibitor is a nucleic acid, and the method is directed to treatment of ischemia or endothelial apoptosis and/or to inducing angiogenesis. The framework includes inhibiting miR-24 and thereby activating direct and indirect miR-24 targets in endothelial cells.
The background problem addressed is ischemia-associated endothelial apoptosis and impaired angiogenesis, including ischemia occurring in conditions such as myocardial infarction and hypoxia. The disclosed findings state that endothelial miR-24 is upregulated after myocardial infarction and hypoxia, and that miR-24 overexpression induces endothelial apoptosis and impairs angiogenic functions including tube/spheroid formation and migration and proliferation.
To connect miR-24 modulation to functional outcomes, the patent establishes a regulatory network in endothelial cells with direct miR-24 targets including GATA2, PAK4, RASA1 and H2AFX, and indirect targets including phosphorylated BAD, HO-1/HMOX1, SIRT1, BAMBI, ESM1 and NTN4. The disclosed outcomes of miR-24 inhibition include reduced endothelial apoptosis and increased capillary/arteriolar density, and the patent further reports supportive evidence from zebrafish vascular phenotypes and endothelial-specific mechanistic rescue using miR-24-resistant target overexpression.
Claims Coverage
Independent claim clm-00001 defines the core claim scope, combining miR-24 inhibition with treatment of ischemia or endothelial apoptosis and/or induction of angiogenesis, and specifies that the miR-24 inhibitor is a nucleic acid. Dependent claims refine the ischemia context and constrain the nucleic-acid inhibitor types and sequence related to SEQ ID NO: 1.
Nucleic-acid miR-24 inhibitor for ischemia, endothelial apoptosis, and angiogenesis
Administering, to a subject in need of such treatment or induction, an inhibitor of microRNA-24 (miR-24), wherein said inhibitor is a nucleic acid, for treatment of ischemia or endothelial apoptosis and/or for inducing angiogenesis.
Treatment for specified ischemic conditions
The method is applied to ischemia associated with one or more specified conditions including acute and/or chronic myocardial infarction, chronic heart failure, peripheral vascular occlusive disease, liver and/or kidney ischemia, stroke, bowel ischemia and chronic skin and/or mucosa ulcers.
Antagomir or antisense oligonucleotide inhibitor
Using an inhibitor that is either an antagomir or an antisense oligonucleotide.
Essentially complementary inhibitor to SEQ ID NO: 1
Using an antagomir or an antisense oligonucleotide that is essentially complementary to SEQ ID NO: 1.
The claim set centers on administering a nucleic-acid inhibitor of miR-24 to treat ischemia or endothelial apoptosis and/or induce angiogenesis, with dependent claims narrowing the ischemic conditions, restricting the inhibitor to antagomir or antisense oligonucleotide, and requiring essential complementarity to SEQ ID NO: 1.
Stated Advantages
Reduces endothelial apoptosis.
Increases capillary/arteriolar density.
Smaller infarct size.
Improved cardiac function and survival.
Documented Applications
Therapeutic treatment of ischemia or endothelial apoptosis and/or induction of angiogenesis, including in contexts such as myocardial infarction and hypoxia.
Use of in vitro diagnostic marker assessment using miR-24 and/or direct/indirect target modulation indicating ischemia.
A cell-based method to identify miR-24 modulators.
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