Nucleic acids for inhibiting expression of TMPRSS6 and iron chelators

1. A combination comprising a nucleic acid for inhibiting expression of TMPRSS6 and one or more iron chelators,

wherein the nucleic acid comprises 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, and wherein said first strand comprises the nucleotide sequence 5′aaccagaagaagcagguga 3′ (SEQ ID NO:17) comprising modifications 6273646282647284546, and wherein said second strand comprises the nucleotide sequence 5′ucaccugcuucuucugguu 3′ (SEQ ID NO:18) comprising modifications 1727354715351718451,

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; and

8=2′-OMe-rG.

2. The combination according to claim 1 , wherein the nucleic acid is conjugated to a ligand, optionally at the 5′ end of the second strand, optionally 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.

3. The combination according to claim 2 , wherein the conjugated nucleic acid has the structure:

wherein Z is a nucleic acid as described in claim 1 .

4. A combination comprising a nucleic acid for inhibiting expression of TMPRSS6 and one or more iron chelators,

wherein the nucleic acid comprises 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 first strand comprises the nucleotide sequence of SEQ ID NO: 333, wherein the nucleic acid is stabilised at the 5′ and/or 3′ end of either or both strands,

optionally 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, having the structure:

(SEQ ID NO: 17)

5′-3′ TMPRSS6-hcm-9A 6(ps)2(ps)736462826472845(ps) 

4(ps)6 

(SEQ ID NO: 18)

5′-3′ TMPRSS6-hcm-9B 17273547153517184(ps)5(ps)1 

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

(ps)=phosphorothioate linkage.

5. The combination according to claim 1 , wherein the one or more iron chelators are selected from deferoxamine, deferiprone, deferasirox (Exjade) and deferairox (Jadenu).

6. The combination according to claim 4 , wherein the one or more iron chelators are selected from deferoxamine, deferiprone, deferasirox (Exjade) and deferairox (Jadenu).

7. The combination according to claim 4 , wherein the nucleic acid is conjugated to a ligand, optionally at the 5′ end of the second strand, optionally 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.

8. The combination according to claim 7 , wherein the conjugated nucleic acid has the structure:

wherein Z is a nucleic acid as described in claim 4 .

9. A kit comprising the combination of claim 1 .

10. A kit comprising the combination of claim 4 .

11. A pharmaceutical composition comprising the combination of claim 1 .

12. A pharmaceutical composition comprising the combination of claim 4 .