Lncrnas for therapy and diagnosis of cardiac hypertrophy

Abstract

The present invention relates to a pharmaceutical composition comprising (i) a compound promoting the expression and/or the activity of one or more long non-coding RNAs (lncRNAs) selected from SEQ ID NOs 12, 8 to 11 and 13; and/or (ii) a compound inhibiting the expression and/or the activity of one or more lncRNAs selected from SEQ ID NOs 1 to 7, 27 and 28. The present invention also relates to a compound (i) promoting the expression and/or the activity of one or more lncRNAs selected from SEQ ID NOs 12, 8 to 11 and 13; and/or (ii) inhibiting the expression and/or the activity of one or more lncRNAs selected from SEQ ID NOs 1 to 7, 27 and 28 for use in treating or preventing cardiac hypertrophy.

1 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a compound inhibiting the expression and/or the activity of the lncRNA of SEQ ID NO: 1,
 wherein the compound is
 (a) a nucleic acid sequence which comprises or consists of a nucleotide sequence being complementary to at least 12 continuous nucleotides of SEQ ID NO: 1, 
 (b) a nucleic acid sequence which comprises or consists of a nucleotide sequence which is at least 69% identical to the complementary strand of the lncRNA of SEQ ID NO: 1, 
 (c) a nucleic acid sequence which comprises or consists of a nucleotide sequence according to (a) or (b), wherein U is replaced by T, 
 (d) an expression vector expressing the nucleic acid sequence as defined in any one of (a) to (c), preferably under the control of a heart-specific promoter, or 
 (e) a host comprising the expression vector of (d). 
   
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the compound is an antisense molecule, siRNA, shRNA, aptamer, ribozyme, antibody, or small molecule. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the siRNA is an 18 to 30 nucleotide-long double-stranded RNA molecule. 
     
     
         19 . The pharmaceutical composition according to  claim 16 , wherein the compound is formulated in a vesicle. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the vesicle is a liposome. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the vesicle is a polymer-based nanoparticle. 
     
     
         22 . The pharmaceutical composition according to  claim 16 , wherein the compound is formulated in an adenoviral vector (AAV) construct. 
     
     
         23 . The pharmaceutical composition according to  claim 20 , wherein the liposome is a cationic liposome. 
     
     
         24 . The pharmaceutical composition according to  claim 16 , wherein the nucleic acid sequence which comprises or consists of a nucleotide sequence of (b) is at least 80%, at least 90%, at least 95%, and at least 99% identical to the complementary strand of the lncRNA of SEQ ID NO: 1. 
     
     
         25 . A method of treating or preventing pathological cardiac hypertrophy in a subject, comprising administering a compound inhibiting the expression and/or the activity of the lncRNA of SEQ ID NO: 1, wherein the compound is
 (a) a nucleic acid sequence which comprises or consists of a nucleotide sequence being complementary to at least 12 continuous nucleotides of SEQ ID NO: 1,   (b) a nucleic acid sequence which comprises or consists of a nucleotide sequence which is at least 69% identical to the complementary strand of the lncRNA of SEQ ID NO: 1,   (c) a nucleic acid sequence which comprises or consists of a nucleotide sequence according to (a) or (b), wherein U is replaced by T,   (d) an expression vector expressing the nucleic acid sequence as defined in any one of (a) to (c), preferably under the control of a heart-specific promoter, or   (e) a host comprising the expression vector of (d).   
     
     
         26 . The method according to  claim 25 , wherein administering of the pharmaceutical composition has a dosage in the range of 0.01 mg to 10 mg per day. 
     
     
         27 . The method according to  claim 25 , wherein the pathological cardiac hypertrophy is a ventricular pathological hypertrophy. 
     
     
         28 . The method according to  claim 27 , wherein the ventricular pathological hypertrophy is a left ventricular pathological hypertrophy. 
     
     
         29 . The method according to  claim 27 , wherein the ventricular pathological hypertrophy is a right ventricular pathological hypertrophy. 
     
     
         30 . A method of diagnosing pathological cardiac hypertrophy in a patient, comprising
 (a) detecting the expression level of the lncRNA of SEQ ID NO: 1 in a sample obtained from said patient, and   (b) comparing said expression level of said lncRNA with the expression level of said lncRNA in a sample obtained from healthy subjects, wherein   a greater than 2-fold upregulation of the lncRNA of SEQ ID NO: 1 in the sample obtained from said patient as compared to the sample obtained from healthy subjects;   is indicative for a pathological cardiac hypertrophy in the patient.   
     
     
         31 . The method according to  claim 30 , wherein said sample is a blood sample or blood-derived sample. 
     
     
         32 . The method according to  claim 30 , wherein said sample is a heart tissue sample. 
     
     
         33 . The method according to  claim 30 , wherein the detection of the expression level of the lncRNA of SEQ ID NO: 1 comprises
 (c) quantitative PCR, preferably quantitative real time PCR, or   (d) a template/RNA amplification method followed by determining the expression level of the lncRNA of SEQ ID NO: 1 using a fluorescence- or luminescence-based quantification method.   
     
     
         34 . The method according to  claim 30 , wherein the method comprises prior to the detection of the expression level of the long non-coding RNA a pre-amplification step of the RNA within the test patient's sample and/or the control patient's sample. 
     
     
         35 . A kit for diagnosing pathological cardiac hypertrophy in a patient, said kit comprising means for the detection of the expression level of the lncRNA of SEQ ID NO: 1, and instructions how to use the kit.