Methods and compositions for the treatment and management of hemoglobinopathy and anemia

• US 20050143420A1
• Filed: 12/02/2004
• Published: 06/30/2005
• Est. Priority Date: 12/02/2003
• Status: Abandoned Application

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Moutouh-de Parseval, Laure, Brady, Helen, Chan, Kyle W.H.
• Application Number:
  US11/004,736
• Publication Number:
  US 20050143420A1
• Time in Patent Office: Days
• US Class Current: 514/323
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics

Abstract

The present invention is directed to the use of immunomodulatory compounds, particularly members of the class of compounds known as IMiDs™, and more specifically the compounds 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione, to induce the expression of fetal hemoglobin genes, genes essential for erythropoiesis, and genes encoding alpha hemoglobin stabilizing protein, within a population of CD34⁺ cells. These compounds are used to treat hemoglobinopathies such as sickle cell anemia or β-thalassemia, or anemias caused by disease, surgery, accident, or the introduction or ingestion of toxins, poisons or drugs.

Claims

1. A method of treating an individual having a hemoglobinopathy or an anemia, said method comprising administering to said individual an immunomodulatory compound in an amount and for a time sufficient to reduce one or more symptoms of said hemoglobinopathy.

2. The method of claim 1, wherein said hemoglobinopathy is sickle cell anemia or thalassemia.

3. The method of claim 1, where said anemia is an anemia induced or related to the administration of a chemotherapy or drug.

4. The method of claim 1, wherein said individual is administered a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of an immunomodulatory compound.

5. The method of claim 4, wherein said immunomodulatory compound is an amino-substituted thalidomide.

6. The method of claim 4, wherein said immunomodulatory compound is α

-(3-aminophthalimido) glutarimide;

an analog or prodrug of α

-(3-aminophthalimido) glutarimide;

3-(4′

aminoisoindoline-1′

-one)-1-piperidine-2,6-dione;

an analog or prodrug of 3-(4′

aminoisoindoline-1′

-one)-1-piperidine-2,6-dione;

or a compound of the formula

7. The method of claim 4, wherein said immunomodulatory compound is 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;

or 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

8. The method of claim 1, additionally comprising treating said individual with a second compound, wherein said second compound is a compound that induces fetal hemoglobin, a compound that relaxes blood vessels, a compound that when covalently bound to hemoglobin S reduces the self-aggregation of hemoglobin S, a compound that is a Gardos channel antagonist, or a compound that reduces red blood cell adhesion.

9. The method of claim 8, wherein said second compound is hydroxyurea, a guanidino derivative, nitrous oxide, butyrate or a butyrate derivative, an aldehyde or an aldehyde derivative, a plant extract having antisickling activity, clotrimazole, a derivative of triarylmethane, a monoclonal antibody or a polyethylene glycol derivative.

10. The method of claim 1, additionally comprising treating said individual with at least one cytokine.

11. The method of claim 10, wherein said at least one cytokine is erythropoietin (Epo);

SCF;

GM-CSF;

Flt-3L;

TNFα

;

IL-3;

or any combination thereof.

12. The method of claim 10, wherein said individual is treated with Epo and SCF.

13. The method of claim 1 wherein said individual is a mammal.

14. The method of claim 13 wherein said individual is a human.

15. The method of claim 10, wherein said treating comprises treating said individual with a combination of stem cell factor (SCF), Flt-3L and IL-3, and subsequently treating sand individual with a combination of SCF and erythropoietin, wherein said treating is sufficient to cause a detectable increase in the expression of at least one fetal hemoglobin gene.

16. A method of modulating the differentiation of a CD34⁺ stem or precursor cell to an erythroid lineage comprising differentiating said cell under suitable conditions and in the presence of an immunomodulatory compound.

17. The method of claim 16, wherein said differentiating is done in the presence of a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of an immunomodulatory compound.

18. The method of claim 17, wherein said immunomodulatory compound is an amino-substituted thalidomide.

19. The method of claim 17, wherein said immunomodulatory compound is α

-(3-aminophthalimido) glutarimide;

an analog or prodrug of α

-(3-aminophthalimido) glutarimide;

3-(4′

aminoisoindoline-1′

-one)-1-piperidine-2,6-dione;

an analog or prodrug of 3-(4′

aminoisoindoline-1′

-one)-1-piperidine-2,6-dione or a compound of the formula

20. The method of claim 17, wherein said immunomodulatory compound is 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;

1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;

1,3 dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;

or 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

21. The method of claim 16, wherein said CD34⁺ stem or precursor cell is a cell in vitro.

22. The method of claim 16, wherein said CD34⁺ stem or precursor cell is a cell in vivo.

23. The method of claim 16, additionally comprising contacting said cell with at least one cytokine.

24. The method of claim 23, wherein said at least one cytokine is erythropoietin (Epo);

SCF;

GM-CSF;

Flt-3L;

TNF-α

;

IL-3;

or any combination thereof.

25. A pharmaceutical composition comprising in a pharmaceutically-acceptable carrier a first immunomodulatory compound and a second compound, wherein said second compound is a compound that induces fetal hemoglobin, a compound that relaxes blood vessels, a compound that when covalently bound to hemoglobin S reduces the self-aggregation of hemoglobin S, a compound that is a Gardos channel antagonist, or a compound that reduces red blood cell adhesion.

26. The method of claim 25, wherein said second compound is hydroxyurea, a guanidino derivative, nitrous oxide, butyrate or a butyrate derivative, an aldehyde or an aldehyde derivative, a plant extract having antisickling activity, clotrimazole, a derivative of triarylmethane, a monoclonal antibody or a polyethylene glycol derivative.

27. A pharmaceutical composition comprising in a pharmaceutically-acceptable carrier an immunomodulatory compound and at least one cytokine, wherein said at least one cytokine is erythropoietin (Epo);

SCF;

GM-CSF;

Flt-3L;

TNF-α

;

IL-3;

or any combination thereof.

28. A method of treating an individual having a hemoglobinopathy or anemia, said method comprising administering to said individual a compound in an amount and for a time sufficient to cause a detectable increase in the level of alpha hemoglobin stabilizing protein (AHSP).

29. The method of claim 28, wherein said compound is an immunomodulatory compound.

30. The method of claim 29, wherein said immunomodulatory compound is a-(3-aminophthalimido) glutarimide or 3-(4′

aminoisoindoline- 1′

-one)-1-piperidine-2,6-dione.