Use of inhibitors and antisense oligonucleotides of BTK for treating proliferative mastocytosis

1. A method for treating proliferative mastocytosis comprising administering a therapeutically effective amount of a Bruton tyrosine kinase (BTK) antisense oligonucleotide or a vector for expressing a BTK antisense oligonucleotide to a mammal having proliferative mastocytosis in need of such treatment, wherein the BTK antisense oligonucleotide is complementary to at least 25 consecutive nucleotides of SEQ ID NO: 2 and wherein the BTK antisense oligonucleotide inhibits expression of BTK in proliferative mast cells and depletes proliferative mast cells.

2. The method according to claim 1 , wherein said antisense oligonucleotide is complementary to at least 30 consecutive nucleotides of SEQ ID NO: 2.

3. The method according to claim 2 , wherein said antisense oligonucleotide targets a start codon region, a coding region, or a 3′-untranslated region of a BTK mRNA, and is able to specifically hybridize with one of said regions and inhibits the expression of BTK.

4. The method according to claim 3 , wherein said antisense oligonucleotide comprises at least one chemical modification selected from modified internucleoside linkage, inverted polarity and nucleotide analogs.

5. The method according to claim 3 , wherein said antisense oligonucleotide is conjugated with at least one group enhancing the bioavailability of the antisense oligonucleotide.

6. The method according to claim 1 , wherein the mammal is a human or a dog.

7. The method according to claim 6 , wherein the proliferative mastocytosis is a category II, III or IV mastocytosis and the mammal is a human.

8. The method according to claim 6 , wherein the proliferative mastocytosis is a mastocytoma and the mammal is a dog.

9. The method according to claim 6 , wherein the proliferative mastocytosis is a solitary mastocytoma and the mammal is a human.

10. The method according to claim 6 , wherein the proliferative mastocytosis is a bullous, erythrodermic or teleangiectatic mastocytosis, mastocytosis with an associated hematological disorder or a myeloproliferative disorder associated with mastocytosis.

11. The method according to claim 6 , wherein the proliferative mastocytosis is a mast cell leukemia.

12. A method for treating a category IV mastocytosis comprising administering to a mammal a therapeutically effective amount of (a) a compound selected from 2-Chloro-T-desoxyadenosine and analogs thereof and (b) a Bruton tyrosine kinase (BTK) inhibitor or a BTK antisense oligonucleotide or a vector for expressing a BTK antisense oligonucleotide to a mammal in need of such treatment, wherein the BTK antisense oligonucleotide is complementary to at least 25 consecutive nucleotides of SEQ ID NO: 2.

13. A method for treating a category III mastocytosis comprising administering to a human a therapeutically effective amount of (a) interferon alpha (IFNα) and (b) a Bruton tyrosine kinase (BTK) inhibitor or a BTK antisense oligonucleotide or a vector for expressing a BTK antisense oligonucleotide to a mammal in need of such treatment, wherein the BTK antisense oligonucleotide is complementary to at least 25 consecutive nucleotides of SEQ ID NO: 2.

14. The method according to claim 1 , comprising administering both a BTK inhibitor and the BTK antisense oligonucleotide.

15. The method according to claim 14 , wherein the BTK inhibitor is selected from malononitrilamides.

16. The method according to claim 15 , wherein the BTK inhibitor is selected from leflunomide analogs.

17. The method according to claim 15 , wherein the BTK inhibitor is selected from:

1-cyano-2-hydroxy-N[4-(methylsulfonyl)phenyl]but-2-enamide, 1-cyano-2-hydroxy-N[3-(methylsulfonyl)phenyl]but-2-enamide, and N[3-bromo-4-(trifluoromethoxy)phenyl]-1-cyano-2-hydroxybut-2-enamide.