Nucleic acids for inhibiting expression of lpa in a cell

Abstract

The present invention relates to products and compositions and their uses. In particular the invention relates to nucleic acid products that interfere with the LPA gene expression or inhibit its expression, preferably for use as treatment, prevention or reduction of risk of suffering cardiovascular disease such as coronary heart disease or aortic stenosis or stroke or any other disorder, pathology or syndrome linked to elevated levels of Lp(a) particles.

1 . A nucleic acid for inhibiting expression of LPA in a cell, comprising at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to at least a portion of RNA transcribed from the LPA gene, wherein said first strand comprises, or preferably consists of, a nucleotide sequence selected from the following sequences: SEQ ID NO: 9, 5, 1, 3, 7, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43,
 wherein the nucleotides at positions 2 and 14 from the 5′ end of the first strand are modified with a 2′ fluoro modification, and the nucleotides on the second strand which correspond to positions 11-13 of the first strand are modified with a 2′ fluoro modification.   
     
     
         2 . The nucleic acid of  claim 1 , wherein all nucleotides of the nucleic acid are modified at the 2′ position of the sugar. 
     
     
         3 . The nucleic acid of any preceding claim, wherein the nucleic acid is modified on the first strand with alternating 2′ O-methyl modifications and 2′ fluoro modifications. 
     
     
         4 . The nucleic acid of any preceding claim, wherein the remaining modifications of the second strand are naturally occurring modifications, preferably 2′ O-methyl. 
     
     
         5 . The nucleic acid of any preceding claim, wherein the nucleic acid comprises a phosphorothioate linkage between the terminal two or three 3′ nucleotides and/or 5′ nucleotides of one or both ends of the first and/or the second strand. 
     
     
         6 . The nucleic acid of any preceding claim, wherein the first strand comprises, or preferably consists of SEQ ID NO: 165 and optionally wherein the second strand comprises, or preferably consists of SEQ ID NO: 163. 
     
     
         7 . The nucleic acid of any of the preceding claims, wherein the nucleic acid is conjugated to a ligand. 
     
     
         8 . The nucleic acid of  claim 7 , wherein the ligand comprises (i) one or more N-acetyl galactosamine (GalNAc) moieties or derivatives thereof, and (ii) a linker, wherein the linker conjugates the at least one GalNAc moiety or derivative thereof to the nucleic acid. 
     
     
         9 . The nucleic acid of any preceding claim, wherein the nucleic acid is conjugated to a ligand comprising a compound of formula (I):
   [S—X 1 —P—X 2 ] 3 -A-X 3 —  (I)
   wherein:
 S represents a saccharide, preferably wherein the saccharide is N-acetyl galactosamine; 
 X 1  represents C 3 -C 6  alkylene or (—CH 2 —CH 2 —O) m (—CH 2 ) 2 — wherein m is 1, 2, or 3; 
 P is a phosphate or modified phosphate, preferably a thiophosphate; 
 X 2  is alkylene or an alkylene ether of the formula (—CH 2 ) n —O—CH 2 — where n=1-6; 
 A is a branching unit; 
 X 3  represents a bridging unit; 
 wherein a nucleic acid as defined in any of  claims 1  to  8  is conjugated to X 3  via a phosphate or modified phosphate, preferably a thiophosphate, and the nucleic acid is preferably conjugated to X 3  via the 5′ end of the second strand. 
   
     
     
         10 . The nucleic acid of any preceding claim, wherein the nucleic acid is conjugated to a ligand and has the following structure 
       
         
           
           
               
               
           
         
         wherein Z is a nucleic acid according any preceding claim and the ligand is preferably conjugated to the 5′ end of the second strand. 
       
     
     
         11 . The nucleic acid of any of  claims 7 - 10 , wherein the nucleic acid comprises two phosphorothioate linkages between each of the three terminal 3′ and between each of the three terminal 5′ nucleotides on the first strand, and two phosphorothioate linkages between the three terminal nucleotides of the 3′ end of the second strand and wherein the ligand is conjugated to the 5′ end of the second strand. 
     
     
         12 . A composition comprising a nucleic acid of any of  claims 1 - 11  and optionally a delivery vehicle and/or a physiologically acceptable excipient and/or a carrier and/or a diluent and/or a buffer and/or a preservative, for use as a medicament, preferably for the prevention or treatment or risk reduction of a disease or pathology, wherein the disease or pathology preferably is a cardiovascular disease, wherein the cardiovascular disease preferably is a stroke, atherosclerosis, thrombosis, a coronary heart disease or aortic stenosis and/or any other disease or pathology associated to elevated levels of Lp(a) particles. 
     
     
         13 . A pharmaceutical composition comprising a nucleic acid of any of  claims 1 - 11  and further comprising a delivery vehicle and/or a physiologically acceptable excipient and/or a carrier and/or a diluent. 
     
     
         14 . Use of a nucleic acid of any of  claims 1 - 11  or a pharmaceutical composition of  claim 13  for the prevention or treatment or risk reduction of a disease or pathology, wherein the disease or pathology preferably is a cardiovascular disease, wherein the cardiovascular disease preferably is a stroke, atherosclerosis, thrombosis, a coronary heart disease or aortic stenosis and any other disease or pathology associated to elevated levels of Lp(a) particles. 
     
     
         15 . A method of preventing or treating a disease, disorder or syndrome comprising administering a composition comprising a nucleic acid of any of  claims 1 - 11  or a composition of any of  claims 12 - 13  to an individual in need of treatment, preferably wherein the nucleic acid or composition is administered to the subject subcutaneously, intravenously or using any other application routes such as oral, rectal or intraperitoneal.