Products and compositions

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 TMPRSS6 gene expression or inhibits its expression and therapeutic uses such as for the treatment of hemochromatosis, porphyria and blood disorders such as β-thalassemias, sickle cell disease and transfusional iron overload or myelodysplastic syndrome.

1 . A nucleic acid for inhibiting expression of TMPRSS6, 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 TMPRSS6 gene, wherein said nucleic acid comprises the following first strand:
 5′-3′: aaccagaagaagcagguga;   optionally wherein the nucleic further comprises the following second strand:   5′-3′: ucaccugcuucuucugguu   
     
     
         2 . A nucleic acid according to any preceding claim, wherein one or more nucleotides on the first and/or second strand are modified, to form modified nucleotides. 
     
     
         3 . A nucleic acid of  claim 2 , wherein said first strand comprises a nucleotide sequence of SEQ ID NO:17, and wherein said second strand comprises the nucleotide sequence of SEQ ID NO:18. 
       
         
           
                 
                 
                 
                 
               
                     
                 
                     
                   SEQ ID 
                   5′aaccagaaga 
                   6273646282647284546 
                 
                     
                   NO: 17 
                   agcagguga 3′ 
                     
                 
                     
                 
                     
                   SEQ ID 
                   5′ucaccugcuu 
                   1727354715351718451 
                 
                     
                   NO: 18 
                   cuucugguu 3′ 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
               
            
           
         
         wherein the specific modifications are depicted by the following numbers 
         1=2′F-dU, 
         2=2′F-dA, 
         3-2′F-dC, 
         4=2′F-dG, 
         5=2′-OMe-rU; 
         6=2′-OMe-rA; 
         7=2′-OMe-rC; 
         8-2′-OMe-rG. 
       
     
     
         4 . A nucleic acid according to any preceeding claim conjugated to a ligand, optionally at the 5′ end of the second strand. 
     
     
         5 . A nucleic acid according to  claim 4  wherein the ligand comprises (i) one or more N-acetyl galactosamine (GalNAc) moieties and derivatives thereof, and (ii) a linker, wherein the linker conjugates the GalNAc moieties to the nucleic acid. 
     
     
         6 . A nucleic acid according to  claim 4  or  5 , wherein linker is a bivalent or trivalent or tetravalent branched structure. 
     
     
         7 . A conjugated nucleic acid according to any of  claims 4 - 6 , having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Z is a nucleic acid according to any of  claims 1  to  40 . 
       
     
     
         8 . A nucleic acid according to any one of  claims 1  to  6 , or a conjugated nucleic according to  claim 7 , wherein the nucleic acid is stabilised at the 5′ and/or 3′ end of either or both strands. 
     
     
         9 . A nucleic acid according to  claim 8  comprising a phosphorothioate linkage between the terminal one, two or three 3′ nucleotides and/or 5′ nucleotides of the first and/or the second strand,
 or comprising 
 a phosphorodithioate linkage. 
 
     
     
         10 . A nucleic acid according to  claim 9  comprising two phosphorothioate linkage 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, having the structure 
       
         
           
                 
                 
                 
               
                     
                 
                   5′-3′ 
                   TMPRSS6- 
                   6 (ps) 2 (ps) 736462826472845 (ps) 4 (ps) 6 
                 
                     
                   hcm-9A 
                     
                 
                   5′-3′ 
                   TMPRSS6- 
                   17273547153517184 (ps) 5 (ps) 1 
                 
                     
                   hcm-9B 
                 
                     
                 
             
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A composition comprising a nucleic acid or conjugated nucleic acid of any preceding claim and a physiologically acceptable excipient. 
     
     
         12 . A nucleic acid or conjugated nucleic acid or composition according to any preceding claim for use in the treatment of a disease or disorder. 
     
     
         13 . Use of a nucleic acid or conjugated nucleic acid or composition according to any preceding claim in the manufacture of a medicament for treating a disease or disorder. 
     
     
         14 . A method of treating a disease or disorder comprising administration of a nucleic acid or composition comprising a nucleic acid or conjugated nucleic acid according to any one preceding claim to an individual in need of treatment. 
     
     
         15 . Use or method according to any of  claims 13 - 14 , or a nucleic acid for use according to  claim 3 , wherein said disease or disorder is selected from the group comprising hemochromatosis, erythropoietic porphyria, transfusional iron overload and blood disorders. 
     
     
         16 . A nucleic acid for use according to  claim 12 , use according to  claim 13  or  15  or a method according to  claim 14  or  15 , wherein the nucleic acid is for one or more or all of:
 (i) treatment of anemia, optionally suitably determined by an increase in haemoglobin; and/or 
 (ii) amelioration of splenomegaly, optionally determined by a reduction of spleen size or weight: and/or 
 (iii) reduction of stressed erythropoiesis in spleen, optionally determined by the proportion of erythroblasts and enucleated erythroid cells determined by FACS analysis, as described herein; and/or 
 (iv) improvement of red blood cell maturation/erythropoiesis in the bone marrow, optionally determined by the proportion of erythroblasts and enucleated erythroid cells determined by FACS analysis.