Modulation of TMPRSS6 expression

1. A method of lowering TMPRSS6 levels, thereby reducing iron accumulation, increasing hepcidin expression levels, and/or decreasing the percentage saturation of transferrin in an animal, comprising administrating to the animal a therapeutically effective amount of an antisense compound targeting TMPRSS6, wherein lowering TMPRSS6 levels reduces iron accumulation, decreases percentage saturation of transferrin and/or increases hepcidin expression levels in a cell or tissue, wherein the antisense compound comprises a single-stranded modified oligonucleotide.

2. A method of treating, preventing, delaying the onset of, ameliorating, and/or reducing a disease, disorder and/or condition, or a symptom thereof, associated with excess accumulation of iron in an animal, comprising administering to the animal a therapeutically effective amount of an antisense compound targeting TMPRSS6, wherein the disease, disorder and/or condition, or the symptom thereof, associated with excess accumulation of iron is treated, prevented, the onset delayed, ameliorated, and/or reduced in the animal, wherein the antisense compound comprises a single-stranded modified oligonucleotide.

3. The method of claim 1 , wherein decreasing transferrin saturation decreases erythropoiesis.

4. The method of claim 3 , wherein the decrease in erythropoiesis treats, prevents, delays the onset of, ameliorates, and/or reduces polycythemia, or symptom thereof, in the animal.

5. The method of claim 2 , wherein the disease, disorder and/or condition is hemochromatosis.

6. The method of claim 2 , wherein the disease, disorder and/or condition is associated with HFE gene mutations, is associated with hemojuvelin gene mutations or is associated with hepcidin gene mutations.

7. The method of claim 2 , wherein the disease, disorder and/or condition is anemia.

8. The method of claim 7 , wherein the anemia is hereditary anemia, myelodysplastic syndrome or severe chronic hemolysis.

9. The method of claim 8 , wherein the hereditary anemia is sickle cell anemia, thalassemia, Fanconi anemia, Diamond Blackfan anemia, Shwachman Diamond syndrome, red cell membrane disorders, glucose-6-phosphate dehydrogenase deficiency, or hereditary hemorrhagic telangiectasia.

10. The method of claim 9 , wherein the thalassemia is β-thalassemia.

11. The method of claim 2 , wherein the disease, disorder and/or condition is iron overload due to transfusion, excess parenteral iron supplement or dietary iron intake.

12. The method of claim 2 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.

13. The method of claim 2 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 90%, at least 95%, at least 99%, or 100% complementary to a human TMPRSS6 nucleic acid.

14. The method of claim 2 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one nucleoside of the modified oligonucleotide comprises a modified sugar or at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

15. The method of claim 14 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

16. The method of claim 14 , wherein the modified sugar is a bicyclic sugar.

17. The method of claim 14 , wherein the modified nucleobase is a 5-methylcytosine.

18. The method of claim 2 , wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxy nucleosides;

a 5′ wing segment consisting of linked nucleosides;

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar and wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

19. The method of claim 2 , wherein the animal is a human.

20. The method of claim 2 , wherein the antisense compound targeting TMPRSS6 reduces accumulation of iron in the animal.

21. The method of claim 2 , wherein the antisense compound targeting TMPRSS6 increases hepcidin expression levels.

22. The method of claim 2 , wherein the antisense compound targeting TMPRSS6 decreases the percentage of saturation of transferrin.

23. The method of claim 2 , further comprising an additional active pharmaceutical agent.

24. The method of claim 23 , wherein the additional agent is a second antisense compound, an iron chelator or hepcidin agonist.

25. The method of claim 24 , wherein the iron chelator is Exjade, Desferal, or Deferiprone.

26. A method of treating, preventing, delaying the onset of, ameliorating, and/or reducing hereditary hemochromatosis and/or β-thalassemia, or a symptom thereof, in an animal, comprising administering to the animal a therapeutically effective amount of a single-stranded modified oligonucleotide targeting TMPRSS6, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxy nucleosides;

a 5′ wing segment consisting of linked nucleosides;

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar, thereby treating, preventing, delaying the onset of, ameliorating, and/or reducing hereditary hemochromatosis and/or β-thalassemia, or the symptom thereof, in the animal.

27. The method of claim 1 , wherein the method reduces TMPRSS6 mRNA expression levels in the liver by at least 65% compared to mRNA expression levels prior to administration of the antisense compound.

28. The method of claim 1 , wherein the antisense compound is conjugated.

29. The method of claim 2 , wherein the antisense compound is conjugated.