38 results about "Beta thalassemia" patented technology

This invention provides vectors (e.g., lentiviral vectors) and expression cassettes for incorporation into vectors for expressing an alpha-globin (α-globin) gene. In certain embodiments method of treatment using such vectors are provided.

The invention relates to the technical field of gene editing, in particular to a composition for treating alpha-thalassemia and application thereof. The composition is used for treating alpha-thalassemia and comprises a gene editing system. By adopting the composition disclosed by the invention, the repair editing of Hb-CS mutation can be realized, the expression of alpha / beta globin can be balanced, and the safety can be ensured.

The invention relates to application of anthraquinone compounds and pharmaceutically acceptable salts thereof in preparation of drugs for treating anemia, the anthraquinone compounds have a structure as shown in formula I. In the formula I, R1-R5 are independently selected from hydrogen, hydroxyl, unsubstituted or hydroxyl-substituted C1-C6 linear or branched alkyl, C1-C6 alkoxy, C1-C6 acyl or-(CH2) n1O (CH2) n2CH3, n1 is selected from 1, 2 or 3, and n2 is selected from 0, 1, 2 or 3. The anthraquinone compound provided by the invention can significantly up-regulate the transcriptional levels of HAMP, EPO and HBG1 genes, has a good treatment effect on thalassemia and beta-sickle anemia, has no significant influence on cell viability and mouse weight, and has medication safety.

The invention discloses a primer group, a kit and a detection system for thalassemia gene detection. In order to more comprehensively and accurately detect point mutation, small insertion, small deletion, gene fusion mutation, large fragment deletion and gene structure variation on a thalassemia core gene and a modified gene in single detection, the invention provides a thalassemia gene detection primer group and a kit. Based on third-generation sequencing platforms such as a single-base nanopore sequencing platform and the like, all point mutation, small insertion, small deletion and gene fusion mutation in the amplification range of the thalassemia core gene and the modified gene can be detected by utilizing the primer group or the kit; and 60 alpha large fragment deletion mutations, 60 beta large fragment deletion mutations and 7 gene structure variations. The method is beneficial to rapid and comprehensive screening of thalassemia, and is high in detection sensitivity and good in accuracy.

The application discloses a pig HBB gene site-directed modification system and application. The application provides a system for site-directed modification of a pig HBB gene, the first carrier, the second carrier and the third carrier contained in the system can express gene editing proteins and sgRNA, three target sites of the HBB gene are effectively cleaved, a site-directed modification fragment of a donor DNA is used to replace a to-be-site-directed modification fragment of the target site, and accurate deletion of bases from 176 to 179 of a CDS sequence of the HBB gene is realized. 41‑42(‑CTTT) The model accurately simulates the most common beta thalassemia mutation genotype beta of Chinese population, provides a precise model for analyzing the pathogenesis of beta thalassemia of Chinese population and developing a new treatment method.

CD39 (CAG>TAG) is one of the most common β0-thalassemic mutation in the Mediterranean area and Latin America, representing >40% of β-thalassemic mutations in Tunisia, Argentina and Italy3. This is a nonsense mutation within the codon of amino acid 39, thus it causes premature translation termination and absence of β-globin4. Here, the inventors exploited adenine base-editors (ABEs) to correct the CD39 (CAG>TAG) mutation in HSPCs from β-thalassemia patients and demonstrated the potential of this strategy to correct the pathological phenotype observed during erythroid differentiation. In particular the inventors demonstrated that reverting the CD39 (CAG>TAG) mutation using base editing corrected in vitro the β-thalassemic cell phenotype in terms of erythroid differentiation, enucleation, RBC size and apoptosis. The present invention thus relates to base editing approaches for the treatment of β-thalassemia, including sickle β-thalassemia.

The present application relates to a primer set for detecting multiple mutations of human embryo beta-thalassemia, a kit and application thereof. The primer set comprises five primers for amplifying HBB a plurality of mutations in the gene region: HBB-F1, HBB-F2, HBB-F3, HBB-R1 and HBB-R2, the sequences of which are shown in SEQ ID NO: 1-5 respectively; and eight primers for amplifying HBB linkage SNP sites within 1Mb range of the upstream and downstream genes: L1-F, L1-R, L2-F, L2-R, L3-F, L3-R, L4-F and L4-R, the sequences of which are shown in SEQ ID NO: 6-13 respectively. Based on the specific combination of long fragment PCR amplification and long fragment high-throughput sequencing, the present application can simultaneously detect multiple mutations of beta-thalassemia in multiple embryo samples with high specificity, accuracy and speed.

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 application belongs to the technical field of biology, and particularly relates to a novel biomarker for screening and diagnosis of beta-thalassemia and application thereof. The application provides a novel polypeptide cluster biomarker for screening and diagnosis of beta-thalassemia based on polypeptides in plasma / serum obtained in vitro from patients, which has the advantages of high sensitivity and high specificity. The biomarker provided by the application can be detected by mass spectrometry, and the detection method is stable and efficient, and does not need to adopt cumbersome steps for inspection, thereby providing laboratory support for screening and diagnosis and treatment of beta-thalassemia.

The application discloses a kit and a detection method for beta thalassemia detection based on multiple CRISPR-LbaCas12a, wherein the kit comprises crRNA specific recognition sequences, and the crRNA specific recognition sequences at least comprise SEQ ID NO: 11 for betaCD41-42 / betaN type, SEQ ID NO: 12 and SEQ ID NO: 13 for betaIVS-II-654 / betaN type, SEQ ID NO: 17 for beta-28 / betaN type, SEQ ID NO: 18 for betaCD17 / betaN type, and SEQ ID NO: 19 for betaCD26 / betaN type. The detection kit and the detection method can realize rapid and portable detection of common mutation types of thalassemia.

The application belongs to the field of biology and particularly relates to a primer blocker composition, a kit, a method for detecting mutation types of beta thalassemia and application thereof. The primer blocker composition comprises a primer group and a blocker, the primer group comprises an upstream primer and a downstream primer, the upstream primer, the downstream primer and the blocker are selected from at least one of combinations I to V, and the blocker is modified with a primary amino group. The specific primer and the blocker are designed based on Gibbs free energy optimization, wild type amplification is selectively inhibited through strict matching of 3' end bases, and high specificity and high sensitivity are shown.

Provided is a method of treating or alleviating one or more pathologies associated with β- thalassemia in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an anti-matriptase-2 antibody or antigen-binding fragment thereof. The one or more pathologies may be insoluble liver iron stores: α-globin precipitates in ery throid cells; reactive oxidized species formation; apoptosis of erythroid cells; reticulocytosis; or a combination thereof.

The present invention relates to products and compositions and their uses. In particular, the invention relates to nucleic acid products that interfere with or inhibit the expression of the TMPRSS6 gene in combination with one or more iron chelators and possibly other active agents, as well as to therapeutic uses such as the treatment of hemochromatosis, porphyria, and blood disorders such as beta-thalassemia, sickle cell anemia, and transfusion iron overload or myelodysplastic syndrome, as well as infections and mortality not related to relapses associated with bone marrow transplantation.

The present invention relates to the treatment of physiologic iron overload and provides antibodies against the proteolysis 2 (MTP-2). Inhibition of MTP-2 reduces dietary iron uptake and reduces iron release from cellular stores in the body. Inhibitors of MTP-2, such as antibodies against the serine protease domain, are useful in the treatment of iron overload, which is characteristic of diseases such as beta-thalassemia and which would otherwise lead to toxic accumulation of iron. Combinations of MTP-2 inhibitors with activin receptor ligand traps or with erythropoietin provide additional therapeutic effects.

The invention discloses an application of chlorbenazolate meglumine in preparation of a medicine for treating hemoglobin abnormality diseases. The chlorbenazolate meglumine can obviously promote the expression of gamma globin in in-vitro research, has no obvious influence on erythroid development, obviously improves the symptoms of anemia, iron overload and the like in a beta-thalassemia mouse model, and shows strong potential for treating diseases caused by beta globin gene deletion or mutation.

The present application relates to a primer set for detecting multiple mutations of human embryo beta-thalassemia, a kit and application thereof. The primer set comprises five primers for amplifying HBB a plurality of mutations in the gene region: HBB-F1, HBB-F2, HBB-F3, HBB-R1 and HBB-R2, the sequences of which are shown in SEQ ID NO: 1-5 respectively; and eight primers for amplifying HBB linkage SNP sites within 1Mb range of the upstream and downstream genes: L1-F, L1-R, L2-F, L2-R, L3-F, L3-R, L4-F and L4-R, the sequences of which are shown in SEQ ID NO: 6-13 respectively. Based on the specific combination of long fragment PCR amplification and long fragment high-throughput sequencing, the present application can simultaneously detect multiple mutations of beta-thalassemia in multiple embryo samples with high specificity, accuracy and speed.

One aspect of the invention is a method for amplifying alpha globin genes HBA1, HBA2 and HBA12 in a single PCR tube to determine an HBA genotype of a subject. This method employs five primers selected to accurate and sensitively identify the HBA1, HBA2, and HBA12, a gene found at a higher frequency in citizens of Saudi Arabia, by accurately annealing to nucleic acids in a biological sample and simultaneously amplifying sequences encoding the alpha globin genes. This invention includes a procedure and required reagents for the amplification of alpha globin genes in a single PCR tube.

The invention belongs to the technical field of biology, and particularly relates to a novel biomarker for screening and diagnosing beta-thalassemia and application of the novel biomarker. The invention provides a novel polypeptide cluster biomarker for screening and diagnosing beta-thalassemia based on polypeptide in plasma / serum obtained in vitro from a patient, and the novel polypeptide cluster biomarker has the advantages of high sensitivity and high specificity. According to the biomarker provided by the invention, detection can be carried out through a mass spectrometry technology, the detection method is stable and efficient, tedious steps for detection are not needed, and laboratory support is provided for screening, diagnosis and treatment of beta-thalassemia.

The invention belongs to the technical field of biology, and particularly relates to an SEA type thalassemia gene detection method based on nucleic acid index isothermal amplification and self-G-tetramer. The invention provides a technology for detecting SEA type thalassemia on the basis of taking a G-tetramer structure as a self-primer and combining a nucleic acid index isothermal amplification technology. The method can be used for detecting gene deletion of the SEA type thalassemia simply, sensitively and high-throughout. At present, a detection system of the SEA type thalassemia gene has been established based on the invention, and the lowest detection limit is about 2fM. The method can be applied to direct detection of other mutation sites of thalassemia.

The invention discloses a method and a composition for activating zeta-globin gene expression. The method comprises artificially forming an enhancer element comprising an NTG-N (7-8)-WGATAR sequence, an NAA-N (7-8)-WGATAR sequence, a YTATCW-N (7-8)-CAN sequence and / or a YTATCW-N (7-8)-CTN sequence on a sense strand or an antisense strand of a non-coding region of a zeta-globin gene by using a gene editing technique. The invention also discloses gRNA, ssODN, a composition and a cell, and application of the gRNA, the ssODN, the composition and the cell in preparation of a medicine for treating alpha-thalassemia. According to the method, overexpression of exogenous globin genes is not needed, and the safety risk of gene therapy is reduced. Moreover, expression of the zeta-globin gene is activated, so that the method can be suitable for various types of alpha-thalassemia patients and alpha-gene deletion or mutation patients, and is not limited to alpha-thalassemia caused by a certain mutation site.

The present invention relates to a polynucleotide construct comprising a hemoglobin subunit alpha-hemoglobin subunit beta (HBA-HBB) hybrid gene construct for enhancing the potency of gene therapy for the β-hemoglobinopathies, particularly β-thalassemia and sickle cell disease (SCD). The polynucleotide construct comprising elements that are operatively connected to each other in the following sequence: HBB locus control region (HBB-LCR), HBA promoter, and β-like globin gene. Additionally, the HBA-HBB gene construct further comprises a microRNA-based short hairpin RNA (shRNAmir) targeting one of the endogenous HBA or HBB genes to increase the ratio of vector-encoded HBBT87Q to endogenous HBA and β-like globin chains while maintaining high vector titers.

The invention further discloses application of a pharmaceutical composition containing the novel compound containing the diaza subunit sulfonyl structure in preparation of drugs for treating anemia-related diseases. The anemia-related diseases may relate to myelodysplastic syndrome (MDS), hemoglobinopathy, sickle-type cell anemia (SCD), beta-thalassemia, hereditary non-spherical cell hemolytic anemia, hemolytic anemia, hereditary spherical polycythemia, hereditary elliptical polycythemia, non-beta lipoproteinemia, paroxysmal nocturnal hemoglobinuria, and the like. Acquired hemolytic anemia or congenital anemia or chronic anemia.

The application discloses a preparation method of a dual-mode CD122 gene thalassemia detection self-powered biosensor, successfully applies an enzyme biological fuel cell (EBFC) to dual-mode detection of CD122 gene thalassemia, realizes quantitative analysis through changes of EBFC output voltage and changes of electrolyte color (RGB Blue value), and mainly concentrates on a cathode of the EBFC in the self-powered design. When CD122 exists, an electrode starts catalytic hairpin self-assembly (CHA) amplification, realizes recycling of CD122, and provides a binding site for subsequent hybridization chain reaction (HCR) amplification, at this time, methylene blue (MB) adsorbed by a biological cathode increases, and an electric signal is enhanced, and meanwhile, electrolyte color becomes lighter (RGB Blue value becomes larger). The self-powered CD122 dual-mode biosensor based on the EBFC disclosed by the application can realize simple, rapid, sensitive and efficient detection of a target.

Enhancing fetal hemoglobin (HbF) production through targeted promoter editing using base editing technologies. An embodiment includes a composition for enhancing fetal hemoglobin (HbF) expression in mammalian cells, the composition comprising a base editing system comprising at least two guide RNAs comprising targeting sequences selected from SEQ ID NO: 1 to SEQ ID NO: 5. Specifically, it involves the design and use of single guide RNAs (sgRNAs) targeting key regulatory elements within the gamma-globin (HBG1 / 2) promoter. The method combines the use of adenosine base editors to introduce mutations, creating new binding sites for transcriptional activators like TAL1 and KLF1, and disrupting repressor binding sites such as BCL11A and ZBTB7A / LRF. This dual-targeting approach significantly increases HbF expression, offering a potential therapeutic strategy for treating beta-hemoglobinopathies like sickle cell disease and beta-thalassemia.

The invention discloses a primer probe combination for beta-thalassemia single-tube multi-gene detection and a kit of beta-thalassemia single-tube multi-gene detection. According to the primer probe combination for single-tube multiple nucleic acid detection based on the nucleic acid invasive reaction and the kit thereof, provided by the invention, mutation type, insertion type and deletion type beta-thalassemia can be detected in a single closed tube at the same time through one test, the operation is simple and convenient, the pollution risk is low, and the single base recognition specificity is strong.

The present disclosure relates to compounds of formula (I) and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels, or inducing fetal hemoglobin (HbF) expression, and in the treatment of inherited blood disorders (e.g., hemoglobinopathies, e.g., beta-hemoglobinopathies), such as sickle cell disease and beta-thalassemia.

Antibodies against the protease 2 (MTP-2) are provided. Inhibition of MTP-2 reduces dietary iron uptake and reduces release of iron from cellular stores in the body. Inhibitors of MTP-2, such as antibodies against the serine protease domain, are useful in the treatment of iron overload, which is characteristic of diseases such as beta-thalassemia and would otherwise result in toxic accumulation of iron. Combinations of MTP-2 inhibitors with activin receptor ligand traps or with erythropoietin provide additional therapeutic effects.

The invention discloses a repair method for alpha thalassemia large-fragment gene deletion, and belongs to the field of biological gene engineering. According to the method, HBA2 genes are successfully placed in gamma-globin gene loci of the iPSCs sourced from the severe alpha-thalassemia Bart's patients through the CRISPR / Cas9 technology, the gamma-globin genes are replaced with the alpha-globin genes, alpha-globin expression of the iPSCs sourced from the severe alpha-thalassemia Bart's patients is recovered, the proportion unbalance degree of alpha- / beta-globin peptide chains is remarkably relieved, and the expression of the gamma-globin gene loci of the iPSCs sourced from the severe alpha-thalassemia Bart's patients is improved. A new treatment direction and thought are provided for effectively treating patients with severe alpha-thalassemia Bart's; according to the repairing method, HBA2 gene expression of severe alpha-thalassemia cells is achieved by placing HBA2 gene in gamma-globin gene loci, the repairing method can be used for repairing the defect of alpha-thalassemia large-fragment gene deletion, effective treatment of severe alpha-thalassemia is achieved, and a more effective and safer treatment scheme can be provided for patients.

Therapeutic methods, systems, and compositions for treating a patient suffering from hemoglobinopathy include treating the patient to increase expression of noncoding RNA activated by DNA damage (NORAD). Overexpression of NORAD long non-coding RNA leads to an increase in fetal hemoglobin expression. The hemoglobinopathy may be β-thalassemia or sickle cell disease.

Provided are gRNA molecules, and nucleic acids, complexes, compositions, cells, and kits thereof. Also provided are methods of increasing the expression level of HbF in progeny erythrocytes of human CD34 + HSPCs by genome editing, which are useful in the treatment of hemoglobinopathies, such as beta-thalassemia and sickle cell disease.