Micrornas and methods of their use

Abstract

Disclosed herein are methods of treating a tumor in a subject, including administering to the subject one or more miRNA nucleic acids or variants (such as mimics or mimetics) thereof with altered expression in the tumor. Also disclosed herein are compositions including one or more miRNA nucleic acids. In some examples, the miRNA nucleic acids are modified miRNAs, for example, and miRNA nucleic acid including one or more modified nucleotides and/or a 5′-end and/or 3′-end modification. In particular examples, the modified miRNA nucleic acid is an miR-30a nucleic acid. Further disclosed herein are methods of diagnosing a subject as having a tumor with altered expression of one or more miRNA nucleic acids. In some embodiments, the methods include detecting expression of one or more miRNAs in a sample from the subject and comparing the expression in the sample from the subject to a control.

We claim: 
     
         1 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of a composition comprising:
 at least one miR-30-5p mimic or mimetic nucleic acid, wherein the miR-30-5p mimic or mimetic nucleic acid comprises:
 (a) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position from the ninth 5′ residue to the nineteenth 5′ residue, when that residue is present in the guide strand; or 
 (b) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises 2′-O-methyl-modified nucleotides at every even position residue, 2′-fluoro-modified nucleotides at every odd position residue, or 2′-O-methyl-modified nucleotides at every odd position residue and 2′-fluoro-modified nucleotides at every even position residue; or 
 (c) a guide strand and a passenger strand, wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; or 
 (d) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position from the ninth 5′ residue to the nineteenth 5′ residue, when that residue is present in the guide strand, and wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; or 
 (e) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises 2′-O-methyl-modified nucleotides at every even position residue, 2′-fluoro-modified nucleotides at every odd position residue, or 2′-O-methyl-modified nucleotides at every odd position residue and 2′-fluoro-modified nucleotides at every even position residue, and wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; 
   
       thereby treating the subject with cancer. 
     
     
         2 . The method of  claim 1 , wherein the miR-30 mimic or mimetic nucleic acid comprises:
 any one of SEQ ID NOs: 37-61, a duplex of SEQ ID NOs: 42 and 56, or a duplex of SEQ ID NOs: 42 and 57; any one of SEQ ID NOs: 73-92, a duplex of SEQ ID NOs: 50 and 61, a duplex of SEQ ID NOs: 73 and 61, or a duplex of SEQ ID NOs: 74 and 61.   
     
     
         3 . The method of  claim 1 , wherein the composition decreases expression of one or more mRNAs listed in Tables 6 to 14. 
     
     
         4 . The method of  claim 1 , wherein the composition is administered in a liposome composition. 
     
     
         5 . The method of  claim 4 , wherein the liposome further comprises one or more molecules targeting the liposome to the cancer. 
     
     
         6 . The method of  claim 5 , wherein the targeting molecule comprises an anti-transferrin receptor antibody or fragment thereof. 
     
     
         7 . The method of  claim 1 , wherein the cancer comprises a squamous cell carcinoma or wherein the cancer is of epithelial origin and is selected from a group of cervical adenocarcinoma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, and pancreatic carcinoma. 
     
     
         8 . The method of  claim 7 , wherein the squamous cell carcinoma comprises head and neck squamous cell carcinoma, lung squamous cell carcinoma, or cervical squamous cell carcinoma. 
     
     
         9 . The method of  claim 1 , further comprising administering one or more additional therapies to the subject. 
     
     
         10 . The method of  claim 9 , wherein the one or more additional therapies comprise surgery, radiation therapy, and chemotherapy. 
     
     
         11 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of a composition comprising:
 at least one miR-30-5p nucleic acid, or a miR-30-5p mimic or mimetic nucleic acid wherein the mimic or mimetic nucleic acid comprises:
 (a) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position from the ninth 5′ residue to the nineteenth 5′ residue, when that residue is present in the guide strand; or 
 (b) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises 2′-O-methyl-modified nucleotides at every even position residue, 2′-fluoro-modified nucleotides at every odd position residue, or 2′-O-methyl-modified nucleotides at every odd position residue and 2′-fluoro-modified nucleotides at every even position residue; or 
 (c) a guide strand and a passenger strand, wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; or 
 (d) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position from the ninth 5′ residue to the nineteenth 5′ residue, when that residue is present in the guide strand, and wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; or 
 (e) a guide strand and a passenger strand, wherein the guide strand is of about 16 to about 27 nucleotides in length and comprises 2′-O-methyl-modified nucleotides at every even position residue, 2′-fluoro-modified nucleotides at every odd position residue, or 2′-O-methyl-modified nucleotides at every odd position residue and 2′-fluoro-modified nucleotides at every even position residue, and wherein the passenger strand is of about 16 to about 27 nucleotides in length and comprises one or more of 2′-O-methyl- and 2′-fluoro-modified nucleotides in any position within the three residues at the 5′ end and the three residues at the 3′ end and a 5′-amino C6 modification; 
   
       thereby treating the subject with cancer, wherein the cancer comprises a squamous cell carcinoma. 
     
     
         12 . The method of  claim 11 , wherein the miR-30 mimic or mimetic nucleic acid comprises:
 any one of SEQ ID NOs: 37-61, a duplex of SEQ ID NOs: 42 and 56, or a duplex of SEQ ID NOs: 42 and 57; any one of SEQ ID NOs: 73-92, a duplex of SEQ ID NOs: 50 and 61, a duplex of SEQ ID NOs: 73 and 61, or a duplex of SEQ ID NOs: 74 and 61.   
     
     
         13 . The method of  claim 11 , wherein the composition decreases expression of one or more mRNAs listed in Tables 6 to 14. 
     
     
         14 . The method of  claim 11 , wherein the composition is administered in a liposome composition. 
     
     
         15 . The method of  claim 14 , wherein the liposome further comprises one or more molecules targeting the liposome to the cancer. 
     
     
         16 . The method of  claim 15 , wherein the targeting molecule comprises an anti-transferrin receptor antibody or fragment thereof. 
     
     
         17 . The method of  claim 11 , wherein the cancer further comprises a cancer of epithelial origin and is selected from a group of cervical adenocarcinoma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, and pancreatic carcinoma. 
     
     
         18 . The method of  claim 11 , wherein the squamous cell carcinoma comprises head and neck squamous cell carcinoma, lung squamous cell carcinoma, or cervical squamous cell carcinoma. 
     
     
         19 . The method of  claim 11 , further comprising administering one or more additional therapies. 
     
     
         20 . The method of  claim 19 , wherein the one or more additional therapies comprise surgery, radiation therapy, and chemotherapy.