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Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters

a technology of fumaric acid and esters, which is applied in the field of methods of treating sickle cell disease and related disorders using fumaric acid esters, can solve the problems of unresponsive or inability to respond well to hu treatment alone, and achieve the effects of increasing hfb expression, improving hu uptake, and improving hu uptak

Inactive Publication Date: 2014-06-19
AUGUSTA UNIV RES INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods for treating sickle cell disease and complications with fumaric acid esters or pharmacologically active salts. These compounds can increase the expression of fetal hemoglobin (HbF) in a subject, which can reduce symptoms of the disease. The methods can involve administering the compounds alone or in combination with other therapeutic agents such as hydroxyurea. The patent also describes methods for increasing HbF expression in retinal pigment epithelial cells and compensating for mutations in the beta-globin gene. The dosage and treatment duration can vary depending on the specific disease being treated. The patent also describes pharmaceutical compositions containing fumaric acid esters and HU for the treatment of sickle cell disease.

Problems solved by technology

In one aspect, the subject treated with the combination of fumaric acid ester and HU is typically unresponsive or does not respond well to HU treatment alone.

Method used

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  • Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters
  • Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters
  • Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters

Examples

Experimental program
Comparison scheme
Effect test

example 1

Monomethylfumarate (MMF) Induces γ-Globin (Hbf) Gene and Protein Expression in Cells of Erythroid Lineage

Materials and Methods

[0191]Pharmaceutical Agents

[0192]The fumaric acid esters dimethylfumarate (DMF) and monomethylfumarate (MMF) are the primary constituents of Fumaderm and BG00012, drugs currently marketed for treatment of psoriasis. BG00012 is also completing phase III clinical testing for treatment of multiple sclerosis. MMF is the major bioactive component of each.

[0193]Cell Culture

[0194]KU812, a human leukemic cell line that expresses the fetal γ-globin and adult β-globin genes, is a commonly used system for screening and discovery of novel HbF inducers; this is because of comparable globin gene response patterns in KU812 and primary erythroid cells after treatments with drug inducers.

Results

[0195]KU812 cells were cultured in the presence or absence of MMF for time periods ranging from 0-24 hours and evaluated for changes in γ-globin gene expression relative to 18S ribosom...

example 2

Monomethylfumarate (MMF) Drives Expression by Activation the γ-Globin (Hbf) Gene Promoter

Materials and Methods

From MaKala et al., Anemia, Volume 2012, Article ID 428137) (2012)

[0197]KU812 Stable Lines

[0198]KU812 stable cell lines were created by co-transfecting wild-type KU812 cells with pEGFP-NI (G418 selectable marker) and the μLCRβprRluc AγprFluc dualreporter a kind gifts from Dr. George Stamatoyannopoulos (University of Washington). Briefly, the 315-bp human β-globin gene promoter sequence was inserted upstream of the Renilla along with a polyadenylation signal downstream to create PβprRluc. Likewise, 1.4 kb of human Aγ-globin promoter was inserted upstream of firefly luciferase to create AγprFluc. The μLCR (locus control region), PβprRluc, and AγprFluc fragments were subsequently cloned into the mammalian vector, pRL-null. The dual-luciferase reporter lines were produced using 10 μg each of linearized μLCRβprRluc AγprFluc and pEGFP-NI plasmids co-transfected into KU812 cells by...

example 3

Dimethylfumarate (DMF) Drives Expression by Activation the γ-Globin (Hbf) Gene Promoter

[0203]MMF is the primary bioactive metabolite derived from metabolism of FUMADERM and BG00012, the fumaric acid ester drugs presently used clinically, and DMF is the primary ingredient. Therefore, the effectiveness of DMF was tested as an inducer of γ-globin gene expression under experimental conditions identical to those described above in Example 2. As with MMF, treatment of cells with DMF also induced γ-globin promoter activity significantly (FIG. 4). At concentrations in the 100-200 μM range, induction of γ-globin promoter activity increased ˜2-10 fold in comparison to control, untreated (UT) cells. However, at higher concentrations the effectiveness of DMF as an inducer of γ-globin promoter activity declined substantially. Trypan blue exclusion revealed that this decrease was likely due to an increase in cellular toxicity as indicated by a decrease in cell viability.

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Abstract

Methods of using one or more fumaric acid esters or pharmacologically active salts, derivatives, analogues, or prodrugs thereof to increase expression of fetal hemoglobin (HbF) are disclosed. The methods typically include administering to a subject an effective amount of one or more fumaric acid esters optionally in combination or alternation with hydroxyurea to induce HbF expression in the subject in an effective amount to reduce one or more symptoms of a sickle cell disorder, a hemoglobinopathy, or a beta-thalassemia, or to compensate for a genetic mutation is the human beta-globin gene (HBB) or an expression control sequence thereof. Pharmaceutical dosage units and dosage regimes for use in the disclosed methods are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Application No. 61 / 737,360, filed Dec. 14, 2012.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under Agreement NEI EY018053 awarded the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The field of the invention is generally related to compositions including fumaric acid esters and methods of their use for HbF (γ-globin gene) induction.BACKGROUND OF THE INVENTION[0004]Sickle-cell disease (SCD), also known as sickle-cell anemia (SCA) and drepanocytosis, is an autosomal recessive genetic blood disorder caused by a point mutation in the β-globin chain of hemoglobin. SCD is characterized by red blood cells that adopt an abnormal, rigid, sickle shape, referred to as “sickling” under low-oxygen conditions. Repeated episodes of sickling can damag...

Claims

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Application Information

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IPC IPC(8): A61K31/225A61K31/17
CPCA61K31/17A61K31/225A61K2300/00
Inventor GANAPATHY, VADIVEL
Owner AUGUSTA UNIV RES INST INC
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