35 results about "Hemoglobinopathy" patented technology

Provided are compositions and methods for the treatment of hemoglobinopathies such as thalassemias and sickle cell disease. Compositions and methods include one or more endonuclease(s) or endonuclease fusion protein(s), including one or more homing endonuclease(s) and / or homing endonuclease fusion protein(s) and / or CRISPR endonuclease(s) ad / or CRISPR endonuclease fusion protein(s): (a) to disrupt a Bcl11a coding region; (b) to disrupt a Bcl11a gene regulatory region; (c) to modify an adult human β-globin locus; (d) to disrupt a HbP silencing DNA regulatory element or pathway, such as a Bcl11a-regulated HbP silencing region; (e) to mutate one or more γ-globin gene promoter(s) to achieve increased expression of a γ-globin gene; (f) to mutate one or more δ-globin gene promoter(s) to achieve increased expression of a δ-globin gene; and / or (g) to correct one or more β-globin gene mutation(s).

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.

The present invention relates to immunomodulatory compounds, in particular a class known as IMiD TM , more specifically the compounds 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione and 3-(4- Use of amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for use in CD34 + The expression of genes for fetal hemoglobin, genes essential for erythropoiesis, and genes encoding alpha hemoglobin stabilizing proteins is induced in the cell population. These compounds are useful in the treatment of hemoglobinopathy, such as sickle cell anemia or beta-thalassemia, or anemia caused by disease, surgery, accident, or the introduction or ingestion of toxins, poisons or drugs.

The presently disclosed subject matter provides for expression cassettes that allow for expression of a globin gene or a functional portion thereof, vectors comprising thereof, and cells transduced with such expression cassettes and vectors. The presently disclosed subject matter further provides methods for treating a hemoglobinopathy in a subject comprising administering an effective amount of such transduced cells to the subject.

Substituted benzimidazole and 3H-imidazo[4,5-b]pyridines or formula I: where X and Y respectively are selected from: (i) N and N; and (ii) N and CR4; A2 is selected from: a C5 heteroarylene group, containing 2 or 3 ring heteroatoms, where the bonds to L1 and the core are β to one another; L1 is selected from: (i) A1—O—CH2—A2; (ii) A1—CH2—O—A2; (iii) A1—C(═O)—NH—A2; (iv) A1—CH(OH)—A2; (v) A1—CH2—NH—C(═O)—A2; (vi) A1—S—CH2—A2; (vii) A1—CH2—S—A2; (viii) A1—CH2—A2; and (ix) A1—CH(CH3)—O—A2; A1 is phenyl, optionally substituted by F or CF3; their use as pharmaceuticals, and in particular, in treating cancer and hemoglobinopathies.

Provided are compositions and methods for the treatment of hemoglobinopathies such as thalassemias and sickle cell disease. Compositions and methods include one or more endonuclease(s) or endonuclease fusion protein(s), including one or more homing endonuclease(s) and / or homing endonuclease fusion protein(s) and / or CRISPR endonuclease(s) and / or CRISPR endonuclease fusion protein(s): (a) to disrupt a Bcl11a coding region; (b) to disrupt a Bcl11a gene regulatory region; (c) to modify an adult human β-globin locus; (d) to disrupt a HbF silencing DNA regulatory element or pathway, such as a Bcl11a-regulated HbF silencing region; (e) to mutate one or more γ-globin gene promoter(s) to achieve increased expression of a γ-globin gene; (f) to mutate one or more δ-globin gene promoter(s) to achieve increased expression of a δ-globin gene; and / or (g) to correct one or more β-globin gene mutation(s).

Recombinant lentiviral vectors having a region encoding a functional β-globin gene; and large portions of the β-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of β-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including β-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than untransformed cells allows selection by treatment of the cells with the corresponding drug.

The present invention provides an assay, suitable for neonatal screening of hemoglobinopathies by quantitatively determining the presence of at least one pair of hemoglobin (Hb) variants, determining the ratio between the signals obtained from each variant; and, based on that ratio, determining whether the tested subject is afflicted or not.

Recombinant lentiviral vectors having a region encoding a functional β-globin gene; and large portions of the β-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of β-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including β-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than untransformed cells allows selection by treatment of the cells with the corresponding drug.

The present invention relates to compounds of formula (I) and (IV), and pharmaceutically acceptable salts, tautomers, stereoisomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are for use in the treatment of disorders that are ameliorated by inhibition of HDAC such as cancer and hemoglobinopathies like β-thalassemia or sickle cell anemia.

The present invention provides compounds (such as compounds of formula I-a) that induce γ globin expression and pharmaceutical compositions thereof. Such compounds may have beneficial therapeutic effects. Compounds and compositions described herein may be used to treat hemoglobinopathies such as β-thalassemia and sickle cell anemia.

A compound of formula Ia, Ib, Ic or Id: wherein: n is 1 or 2; RN is H or Me; R1 is optionally one or more halo or methyl groups; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d (if present) are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R3a and R3b are independently selected from H and Me; R4a is selected from OH, —NH2, —C(═O)NH2, and —CH2OH; R4b is either H or Me; R5 is either H or Me; m is 1 or 2; q is 0 or 1; R11a, R11b, R11c and R11d are independently selected from H, halo, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C1-4 alkyloxy, NH—C1-4 alkyl and cyano; R12a and R12b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R12c and R12d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R12e is H or Me; R13a and R13b are independently selected from H and Me; R14 is either H or Me; R16a and R16b are independently selected from H and Me; R6 is selected from H, OMe, and OEt.

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.

The present invention provides compositions comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, wherein the compositions are useful to induce differentiation of cells or to stimulate differentiation or production of pluripotent cells. The present invention provides methods of using these compositions to induce differentiation of pluripotent cells, including bone marrow derived cells, and to treat disease associated with insufficient differentiation of cells in animals and humans, including but not limited to leukemia, lymphoma, non-malignant blood disorders such as hemoglobinopathies, sickle cell disease, myelodysplastic syndrome, pancytopenia, anemia, thrombocytopenia and leukopenia.