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

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.

We claim: 
     
         1 . A method of increasing fetal hemoglobin (HbF) expression in a subject in need thereof comprising administering to the subject an effective amount of a fumaric acid ester, or pharmacologically active salt, derivative, analogue, or prodrug thereof to increase fetal hemoglobin (HbF) expression, to induce expression of OCTN1 in the erythroid or retinal cells of the subject, or a combination thereof in the subject. 
     
     
         2 . The method of  claim 1 , wherein the fumaric acid ester is selected from the group consisting of monomethyl fumarate (MMF), dimethyl fumarate (DMF), and a combination thereof. 
     
     
         3 . The method of  claim 1 , further comprising administering hydroxyurea (HU) to the subject in combination or alternation with the fumaric acid ester or pharmacologically active salt, derivative, analogue, or prodrug thereof. 
     
     
         4 . The method of  claim 3 , wherein the subject does not express increased levels of HbF when treated with HU alone compared to when treated with the fumaric acid ester or pharmacologically active salt, derivative, analogue, or prodrug thereof and HU in combination or alternation. 
     
     
         5 . The method of  claim 1  wherein the subject has one or more mutations in in the beta-globin gene (HBB gene) or an expression control sequence thereof. 
     
     
         6 . The method of  claim 1  wherein the subject has sickle cell disease. 
     
     
         7 . The method of  claim 1  wherein the subject has sickle cell anemia. 
     
     
         8 . The method of  claim 1  wherein the subject has a beta-thalassemia. 
     
     
         9 . The method of  claim 1  wherein the subject has a sickle cell related disorder. 
     
     
         10 . The method of  claim 1  wherein the subject has sickle cell retinopathy. 
     
     
         11 . The method of  claim 1  wherein the subject has one or more symptoms of a beta-thalassemia, a hemoglobinopathy, or sickle cell disease. 
     
     
         12 . The method of  claim 11  wherein the subject has one or more symptoms of a beta-thalassemia selected from the group consisting of anemia, fatigue and weakness, pale skin, jaundice, protruding abdomen, enlarged spleen and liver, dark urine, abnormal facial bones, poor growth, poor appetite. 
     
     
         13 . The method of  claim 1  wherein the subject has one or more symptoms of the sickle cell disease is selected from the group consisting of chronic hemolytic anemia, vaso-occlusive crisis, infarction of bone and bone marrow, compensatory bone marrow hyperplasia, secondary osteomyelitis, secondary growth defects, intravascular thrombosis, osteonecrosis, degenerative bone and joint destruction, osteolysis, articular disintegration, myelosclerosis, periosteal reaction, H-shaped vertebrae, dystrophic medullary calcification, bone-within-bone appearance, decreased density of the skull, decreased thickness of outer table of skull due to widening of diploe, hair on-end striations of the calvaria, osteoporosis sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, pathologic fractures, bone shortening, epiphyseal deformity with cupped metaphysis, peg-in-hole defect of distal femur, decreased height of vertebrae, hematuria, proximal tubule dysfunction, impaired potassium excretion, hyperkalemia, hypertrophied kidney, spleen enlargement, splenic sequestration crisis, infarction, low pH and low oxygen tension in the sinusoids and splenic cords, spleen functional impairment, autosplenectomy, immune deficiency, increased risk of sepsis, lower serum immunoglobulin M (IgM) levels, impaired opsonization, sluggish alternative complement pathway activation, increased susceptibility to infection pneumonia, bronchitis, cholecystitis, pyelonephritis, cystitis, osteomyelitis, meningitis, sepsis and other challenges from infectious agents, growth delays, maturation delays during puberty in adolescents, hand-foot syndrome, acute chest syndrome, stroke, hemiparesis, hemosiderin deposition in the myocardium, dilation of both ventricles and the left atrium, cholelithiasis, paraorbital facial infarction, retinal vascular changes, proliferative retinitis, loss of vision, leg ulcers, priapism, avascular necrosis, and pulmonary hypertension. 
     
     
         14 . A method of increasing HbF expression in hemoglobin producing cells comprising contacting the cells with an effective amount of a fumaric acid ester, or pharmacologically active salt, derivative, analogue, or prodrug thereof to increase HbF expression, to induce expression of OCTN1, or a combination thereof in the cells. 
     
     
         15 . The method of  claim 14  further comprising contacting the cells with hydroxyurea. 
     
     
         16 . The method of  claim 14  wherein the contacting occurs in vitro. 
     
     
         17 . The method of  claim 14  wherein the contacting occurs in vivo. 
     
     
         18 . The method of  claim 14  wherein the cells are erythroid precursor cells, macrophage, retinal pigment cells, or alveolar epithelial cells. 
     
     
         19 . A method for treating sickle cell disease comprising administering to a subject in need thereof an effective amount of fumaric acid ester, or pharmacologically active salt thereof to increase fetal hemoglobin (HbF) expression in the subject. 
     
     
         20 . The method of  claim 19 , further comprising administering an effective amount of hydroxyurea to the subject.