Compositions for use in treating or diagnosing bone disorders and/or cardiovascular disorders

Abstract

Compositions of an inhibitor of a polynucleotide for use in treating or preventing bone disorders such as osteoporosis, osteopenia, bone fracture, bone cancer, as well as impaired bone homeostasis. Preferred compounds to be used in these medical interventions are antagonistic compounds, like nucleic acid molecules, directed against miR-31 and derivatives thereof. Also, methods for diagnosing and compositions for use in diagnosing bone disorders. Compounds to be employed in these diagnostic methods and uses include compounds such as miR-31.

1 .- 23 . (canceled) 
     
     
         24 . Composition comprising an antagonist/inhibitor of a polynucleotide, wherein said polynucleotide is capable of decreasing or suppressing expression of FZD3 or a biologically active derivative thereof; and/or an antagonist/inhibitor of miR-31 or its 5′ or 3′ isoforms or variants, for use in treating or preventing bone disorders in a subject or for diagnosing bone disorders in a subject or for use in monitoring in vitro the treatment success of a bone disorder. 
     
     
         25 . The composition according to  claim 24 , wherein the polynucleotide to be antagonized/inhibited is selected from the group consisting of microRNA, siRNA, mimic microRNA, long non-coding RNAs, snRNA, stRNA, fRNA, snRNA, snoRNA. piRNA, tasiRNA, aRNA and a precursor of such polynucleotides. 
     
     
         26 . The composition according to  claim 24 , wherein the polynucleotide to be antagonized/inhibited is one of about 15 to about 100, about 18 to about 27 or about 20 to 24 nucleotides in length. 
     
     
         27 . The composition according to  claim 24 , wherein the polynucleotide to be antagonized/inhibited or wherein the miR-31 or its 5′ or 3′ iso forms or variants are selected from the group consisting of:
 (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1; 
 (b) a polynucleotide which is at least 80% identical to the polynucleotide of (a); 
 (c) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 2; and 
 (d) a polynucleotide according to (b) comprising the nucleotide sequence of SEQ ID NO: 2. 
 
     
     
         28 . The composition according to  claim 27 , wherein the composition comprises one, two, three or more inhibitors of one, two, three or more of any one of polynucleotides (a) to (d). 
     
     
         29 . The composition according to  claim 24 , wherein the polynucleotide to be antagonized/inhibited is miR-31 or its 5′ or 3′ isoforms or variants. 
     
     
         30 . The composition according to  claim 24 , wherein the composition contains about 1 ng/kg body weight to about 10 mg/kg body weight of the antagonist/inhibitor. 
     
     
         31 . The composition according to  claim 24 , wherein the antagonist/inhibitor of the miR-31 or its 5′ or 3′ isoforms or variants is comprised in a lipid composition, an exosome or a liposome. 
     
     
         32 . The composition according to  claim 24  further comprising a pharmaceutically acceptable carrier. 
     
     
         33 . The composition according to  claim 24 , wherein the antagonist/inhibitor is capable of hybridizing to miR-31 or to its 5′ or 3′ isoforms or variants. 
     
     
         34 . The composition according to  claim 24 , wherein the antagonist/inhibitor is selected from the group consisting of antagomiRs, miRCURY LNA™ microRNA inhibitors, in vivo LNA™ miR inhibitors, tiny LNA, or miR-decoys or miR-sponges. 
     
     
         35 . The composition of claim  15 , wherein the antagomiRs, miRCURY LNA™ microRNA inhibitors, in vivo LNA™ miR inhibitors, tiny LNA, or miR-decoys or miR-sponges comprise a nucleic acid molecule or include a nucleic acid sequence selected from the group consisting of:
 (a) a nucleic acid sequence being or comprising SEQ ID NO: 5; 
 (b) a nucleic acid sequence being or comprising SEQ ID NO: 6; 
 (c) a nucleic acid sequence being or comprising SEQ ID NO: 7; 
 (d) a nucleic acid sequence being or comprising SEQ ID NO: 8; and 
 (e) a nucleic acid sequence which is at least 90% identical to the nucleic acid sequence of any one of (a) to (d).) 
 
     
     
         36 . A method for diagnosing bone disorders in a subject, which method comprises:
 (a) contacting a biological sample from said subject with a nucleic acid molecule which hybridizes to a polynucleotide being capable of decreasing or suppressing expression of FZD3 and/or which hybridizes to miR-31 or its 5′ or 3′ isoforms or variants, or contacting said biological sample with an agent that binds to said polynucleotide being capable of decreasing or suppressing expression of FZD3 and/or that binds to miR-31 or its 5′ or 3′ isoforms or variants;   (b) detecting and evaluating the hybridization signal of the nucleic acid molecule of (a) or detecting and evaluating the binding signal of the agent of (a) with said polynucleotide and/or said miR-31 or its 5′ or 3′ isoforms or variants; and   (c) comparing the detected and evaluated hybridization signal of (b) or comparing the detected and evaluated binding signal of (b) with a correspondingly detected and evaluated hybridization or binding signal in a control sample,   wherein a stronger hybridization signal or a stronger binding signal in the sample of the subject compared to that of said control sample is indicative for a risk of developing or having a bone disorder.   
     
     
         37 . A method for diagnosing bone disorders and/or cardiovascular disorders in a subject, which method comprises:
 (a) detecting via a PCR method the expression level and/or quantity of miR-31 (or of isoforms and variants thereof) in a biological text sample; and   (b) comparing the detected expression level and/or quantity of the miR-31 (or of the isoforms and variants) in the biological sample with a corresponding expression level and/or quantity of the miR-31 in a control sample.   
     
     
         38 . The method according to  claim 37 , wherein the hybridizing nucleic acid molecule or the binding agent is conjugated with a marker molecule and/or a tagging molecule. 
     
     
         39 . The method according to  claim 37 , wherein the agent to be employed is a specific protein or protein fragment. 
     
     
         40 . The method according to  claim 39 , wherein the specific protein or protein fragment is an antibody or a fragment thereof or is a modified transcription factor capable of binding to and/or interacting with polynucleotide that is capable of binding to and/or interacting with miR-31 or its 5′ or 3′ isoforms or variants.) 
     
     
         41 . A method for treating or preventing bone disorders and/or cardiovascular disorders in a subject, the method comprising administering an effective amount of a composition according to  claim 24  to a subject in need thereof. 
     
     
         42 . The method according to  claim 41 , wherein the bone disorder is selected from the group consisting of osteoporosis, osteopenia, bone fracture, and impaired bone homeostasis. 
     
     
         43 . The method according to  claim 41 , wherein the composition is administered via injection, via inhalation, orally, rectal, vaginally, topically or locally.