MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES

• US 20110182867A1
• Filed: 09/14/2009
• Published: 07/28/2011
• Est. Priority Date: 09/15/2008
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Children's Medical Center Corporation, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Sankaran, Vijay G., Orkin, Stuart H.
• Granted Patent: US 8,383,604 B2
• Time in Patent Office: Days
• US Class Current: 424/93.7
• CPC Class Codes: A01K 2217/052 inducing gain of function
• CPC Class Codes: A01K 2217/15 Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0381 Animal model for diseases of the hematopoietic system
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/805 Haemoglobins; Myoglobins
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 2501/60 Transcription factors
• CPC Class Codes: C12N 2501/998 Proteins not provided for elsewhere
• CPC Class Codes: C12N 2740/15043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2800/206 : of yeast origin, e.g. YAC, 2u
• CPC Class Codes: C12N 5/0647 : Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies.

Claims

1. A method for increasing fetal hemoglobin levels in a cell, the method comprising the steps of contacting a hematopoietic progenitor cell with an effective amount of a composition comprising an inhibitor of BCL11A, whereby fetal hemoglobin expression is increased in said cell, or its progeny, relative to said cell prior to said contacting.

2. The method of claim 1, wherein the hematopoietic progenitor cell is a cell of the erythroid lineage.

3. The method of claim 1, wherein the hematopoietic progenitor cell is contacted ex vivo or in vitro.

4. The method of claim 1, wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A expression.

7. The method of claim 4, wherein the inhibitor of BCL11A comprises a BCL11A specific RNA interference agent that comprises one or more of the nucleotide sequences of SEQ ID NO:

1-6.

8. The method of claim 1, wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A activity.

11. The method of claim 8, wherein the inhibitor of BCL11A comprises a BCL11A specific RNA interference agent that comprises one or more of the nucleotide sequences of SEQ ID NO:

1-6.

5. (canceled)

6. (canceled)

9. (canceled)

10. (canceled)

12. A method for increasing fetal hemoglobin levels in a mammal in need thereof, the method comprising the step of contacting a hematopoietic progenitor cell in said mammal with an effective amount of a composition comprising an inhibitor of BCL11A, whereby fetal hemoglobin expression is increased in said mammal, relative to expression prior to said contacting.

13. The method of claim 12, wherein said mammal has been diagnosed with a hemoglobinopathy.

14. The method of claim 13, wherein said hemoglobinopathy is a β

-hemoglobinopathy.

15. The method of claim 13, wherein the hemoglobinopathy is sickle cell disease.

16. The method of claim 13, wherein the hemoglobinopathy is β

-thalassemia.

17. The method of claim 12, wherein the hematopoietic progenitor cell is contacted ex vivo or in vitro, and said cell or its progeny is administered to said mammal.

20. The method of claim 12, wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A expression.

23. The method of claim 20, wherein the inhibitor of BCL11A comprises a BCL11A specific RNA interference agent that comprises one or more of the nucleotide sequences of SEQ ID NO:

1-6.

24. The method of claim 12, wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A activity.

27. The method of claim 24, wherein the inhibitor of BCL11A comprises a BCL11A specific RNA interference agent that comprises one or more of the nucleotide sequences of SEQ ID NO:

1-6.

18. (canceled)

19. (canceled)

21. (canceled)

22. (canceled)

25. (canceled)

26. (canceled)

28. A method for identifying a modulator of BCL11A activity or expression, the method comprising contacting a hematopoietic progenitor cell with a composition comprising a test compound, and measuring the level of fetal hemoglobin or fetal hemoglobin mRNA in said cell or its progeny, wherein an increase in fetal hemoglobin is indicative that said test compound is a candidate inhibitor of BCL11A activity or expression.

29. The method of claim 28, wherein the hematopoietic progenitor cell is contacted in vivo, ex vivo, or in vitro.

31. The method of claim 28, wherein the test compound is a small molecule, antibody or nucleic acid.

32. The method of claim 28, wherein the composition causes an increase in fetal hemoglobin mRNA or protein expression.

30. (canceled)