30 results about "GDF15" patented technology

This disclosure generally relates to methods and compositions for functional genetic modifications at selected genomic sites, such as the FGF21 gene or the GDF15 gene. This disclosure further provides compositions and methods for genomic editing of AU-rich elements in the FGF21 and / or GDF15 genes for treating obesity-related diseases and disorders.

In some aspects, the invention teaches pharmaceutical compositions that include a TGF-β ligand trap, and methods of using a TGF-β ligand trap to treat, prevent, or reduce the progression rate of pulmonary hypertension (PH). The invention also provides methods of using a TGF-β ligand trap to treat, prevent, or reduce the progression rate of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, right ventricular hypertrophy, diseases associated with excessive TGF-β signaling, diseases associated with excessive GDF15 signaling, and diseases associated with excessive PAI-1 signaling. The invention further provides methods of using a TGF-β ligand trap to reduce right ventricular systolic pressure in a subject.

A GDF15 binding molecule, in particular an antibody and fragments thereof that specifically recognize GDF15. Nucleic acids or host cells comprising such antibodies or fragments thereof, medicaments comprising such antibodies or fragments thereof, and therapeutic and diagnostic methods or uses applying these antibodies and fragments.

The objective is to provide a simple and indirect method for estimating the rate of senescent immune cells (the ratio of immune cells with high SAβgal expression levels among T cells whose surface marker is CD8-positive) using a small amount of blood sample. [Solution] This method estimates the rate of senescent immune cells using the relative expression levels of one or more selected from Granzyme K, α-Klotho, GDF15, PAI-1 (SERPIN1), and ferritin in the blood.

The present invention provides a GDF15-binding nanoantibody, and a use thereof in preparation of a drug for treating tumor cachexia and in detection of GDF15. The nanoantibody provided in the present invention exhibits high affinity for GDF-15 and is capable of blocking the binding of GDF-15 to GFRAL.

This invention belongs to the field of biomedical technology, specifically relating to a GDF15 antagonistic peptide and its application. The amino acid sequence of the antagonistic peptide is shown in SEQ ID NO.1. To improve drug stability and blood-brain barrier penetration, GDF15-A-Pep was fused with albumin and transferrin receptor nanobodies. Biological validation results showed that the fusion protein significantly inhibited GDF15-induced MMP1 transcription and protein expression, and exhibited potent antagonistic activity in reporter gene experiments. This invention not only reveals the key structural basis of GDF15 receptor recognition but also provides experimental evidence for the development of novel GDF15 antagonistic drugs with central regulatory potential.

The invention provides a Crohn disease early screening marker based on plasma proteomics. The early screening marker comprises the following nine proteins: CD274, CHI 3L1, REG1B, ITGAV, PRSS8, ITGA11, GDF15, DEFA1DEFA1B and IL6. The early screening marker provided by the invention can accurately and non-invasively predict CD as long as 16 years before diagnosis, which provides an important value for early screening of CD high risk groups and formulation of intervention measures. The invention also provides application of the Crohn disease early screening marker and an early screening kit for Crohn disease prediction.

The invention provides a COPD (chronic obstructive pulmonary disease) early screening marker based on plasma proteomics. The early screening marker comprises the following ten proteins: CXCL17, WFDC2, SCGB1A1, GDF15, EDA2R, TNR, AGER, CA14, ODAM and TNFRSF10B. The early screening marker provided by the invention can provide ultra-early warning within 16 years before disease attack, is high in prediction accuracy, and is superior to the conventional model in short-term and long-term prediction aspects; meanwhile, a key proteome pathway is disclosed, and reference can be provided for clinical application and prevention strategies. The invention also provides application of the chronic obstructive pulmonary disease early screening marker and a corresponding early screening kit.

The application discloses application of growth differentiation factor 15 in preparation of products for diagnosis, prognosis and treatment of retinal arterial obstruction, and finds that serum GDF15 level of a patient with RAO is greater than or equal to 442.64 pg / mL, and is significantly positively correlated with the risk of RAO (OR=12.6), and the diagnostic accuracy can be improved by combining glucose, triglyceride and other indexes (AUC=0.922). The recombinant human GDF15 protein can inhibit ischemia and hypoxia RGC apoptosis and protect visual function. The application has important application value in early diagnosis of RAO, visual prognosis evaluation and targeted treatment.

Provided in the present invention is an antibody or fragment thereof against a human growth and differentiation factor 15 protein (GDF15). Further provided in the present invention is the use of the antibody or fragment thereof in the preparation of a drug for treating diseases or conditions. The antibody or fragment thereof provided in the present invention can bind to human GDF15 with high affinity and specificity, blocks the interaction of GDF15 with receptor GFRAL thereof, and has a longer half-life period in vivo in comparison with antibodies of the same kind.

The invention provides a liver cirrhosis complication early screening marker based on plasma proteomics. The liver cirrhosis complication early screening marker comprises the following five proteins: GDF15, NOTCH2, PROC, GGT1 and COL4A1. The early screening marker provided by the invention can provide ultra-early warning within 16 years before disease attack, is high in prediction accuracy, and is superior to the conventional model in short-term and long-term prediction aspects; meanwhile, a key proteome pathway is disclosed, and reference can be provided for clinical application and prevention strategies. The invention also provides application of the liver cirrhosis complication early screening marker and a corresponding early screening kit.

This invention relates to the field of biomedical technology. It provides a cardiac-targeting bispecific antibody protein and its applications. The bispecific antibody protein comprises a targeting conjugate that specifically recognizes NPR1 and a sequence that specifically recognizes GDF15. The amino acid sequence of the bispecific antibody protein is shown in SEQ ID NO.2. This invention cleverly achieves the dual functions of cardiac tissue targeting and effectively mediating endocytosis by utilizing a membrane protein specifically highly expressed in myocardial tissue as an effector molecule. The cardiac-targeting bispecific antibody protein of this invention can target the cardiac tissue surface receptor NPR1 and specifically target and degrade GDF15 within cardiac tissue, showing promising application prospects in the treatment of heart failure.

The present disclosure provides a method of treating cardiometabolic syndrome (CMS) with a GDF15 molecule. Also provided herein is a method of treating a cardiac or heart condition. In some embodiments, the GDF15 molecule is a GDF15-Fc fusion, in which a GDF15 region is fused to an Fc region, optionally via a linker.

This invention proposes an antibody or antigen-binding fragment thereof that binds to GDF15. The antibody or antigen-binding fragment comprises: a CDR sequence selected from at least one of the following or an amino acid sequence having at least 66% identity with it: heavy chain variable region CDR sequence: SEQ ID NO: 1-34 and SEQ ID NO: 74-76; light chain variable region CDR sequence: SEQ ID NO: 36-73 and SEQ ID NO: 77-82. According to embodiments of the invention, the antibody or antigen-binding fragment thereof can specifically bind to GDF15 and effectively block the binding of GFRAL and GDF15, while also effectively inhibiting Treg differentiation, and can be used for the prevention and / or treatment of cancer and cachexia.

This invention discloses GDF15 micro-binding agents and their applications. This application provides a novel class of micro-binding agents specifically targeting the GDF15-GFRAL signaling pathway. These micro-binding agents possess extremely high binding affinity, excellent structural stability, and good in vitro and in vivo functional activity. Experiments show that these micro-binding agents can significantly reverse cancer-related cachexia in various tumor models, restore body weight, and prolong survival; simultaneously, they can restore sensitivity to PD-1 immune checkpoint inhibitors and enhance CD8... + The infiltration and function of T cells in the tumor microenvironment have broad clinical application prospects.

The invention provides a liver complication early screening marker based on plasma proteomics. The liver complication early screening marker comprises the following nine proteins: GDF15, PROC, GGT1, ANXA10, IL18, MFAP4, COL4A1, CDCP1 and IL6. The early screening marker provided by the invention can provide ultra-early warning within 16 years before disease attack, is high in prediction accuracy, and is superior to the conventional model in short-term and long-term prediction aspects; meanwhile, a key proteome pathway is disclosed, and reference can be provided for clinical application and prevention strategies. The invention also provides application of the liver complication early screening marker.

This disclosure provides combination therapy with GDF15 molecules. In some embodiments, the GDF15 molecule is a GDF15-Fc fusion, wherein a GDF15 region is fused to an Fc region, optionally via a linker. In one embodiment, the combination therapy comprises the administration of a GDF15 molecule with a GLP-1R agonist. In another embodiment, the combination therapy comprises the administration of a GDF15 molecule with a GIPR antagonist.

This invention discloses a method for constructing a predictive model for heart failure and all-cause mortality risk in patients with chronic kidney disease (CKD). It relates to the field of model construction technology, and its key technical points are as follows: This invention uses G3a-G5 stage CKD patients with preserved ejection fraction as the research subjects, establishes a prospective cohort, collects clinical indicators, biomarkers, and quality of life scores, and uses new-onset heart failure combined with all-cause mortality as the composite endpoint. After standardized follow-up and data preprocessing, univariate Cox regression, Lasso, random forest, XGBoost combined with Venn diagrams are used to screen predictive factors. Age, lipoprotein(a), ferritin, GDF15, and EQ-5D quality of life score are identified as independent predictors. A time-dependent nomogram model is constructed, and multi-dimensional efficacy validation is performed. This model is adapted to the specific pathophysiological state of CKD, with accurate predictions and good calibration. With accompanying online interactive tools, it can achieve individualized risk assessment and stratified intervention for 24-36 months, solving the problems of poor applicability and inaccurate prediction in existing models, and has strong clinical applicability.

The application relates to the technical field of biological medicine engineering, and relates to an aptamer specifically combined with GDF15, a sequence general formula of which is as follows: 5'-AGCAGCACAGAGGTCAGATG-N 40 -CCTATGCGTGCTACCGTGAA-3'; wherein N is any one of A, T, G and C, four deoxyribonucleotide bases, 40 represents the number of random bases, and the sequence is preferably as shown in any one of SEQ ID NO. 1-4. The aptamer has wide application prospects and can be used for GDF15 capture in a system, GDF15 detection in and out of a body, development of GDF15 therapeutic drugs in related diseases and construction of a targeted drug delivery system and the like. The aptamer has great potential for practical application.

The embodiment of the invention discloses application of a growth differentiation factor 15 in preparation of a product for treating retinal artery occlusion. In-vitro and in-vivo experiments prove that the GDF15 has the potential of directly treating RAO: in an ischemia and hypoxia R28 cell model, the cell activity can be remarkably improved and apoptosis can be inhibited by the treatment of the recombinant human GDF15 protein. In an RAO mouse model, the GDF15 treatment can promote the survival of retinal ganglion cells and increase the thickness of a nerve fiber layer, and shows a clear eyesight protection effect. The product preferably contains recombinant human GDF15 protein, can inhibit cell death paths caused by ischemia and hypoxia in a targeted manner, and improves pathological changes such as retinal endoedema and tissue atrophy. The invention discloses the direct application of GDF15 as a therapeutic agent in RAO for the first time, provides an experimental basis for developing related drugs, and has important clinical application value in the field of ophthalmic emergency treatment.

The present application discloses two anti-GDF15 neutralizing monoclonal antibodies and uses thereof. The variable regions of the light chain and heavy chain of the antibodies G1 and G2 with neutralizing activity are provided. Anti-GDF15 mouse monoclonal antibodies were prepared by the hybridoma technology, anti-GDF15 hybridoma cell lines capable of stable secretion with high specificity were screened out, ascites were prepared to obtain high-specificity and high-affinity anti-GDF15 monoclonal antibodies and two anti-GDF15 monoclonal antibodies with neutralizing activity were identified for the first time by constructing an antibody neutralization detection system. On the basis of the study of immune regulation of GDF15, the inhibitory effect of the neutralizing monoclonal antibodies on tumor growth is verified by establishing a co-culture system of lymphocytes and tumor cells and the tumor-bearing experiment in mice, which lays a foundation for humanization of antibodies and the use thereof in tumor immunotherapy and metabolism related diseases.

To provide anti- GDF15 antibodies useful for the treatment of diseases or symptoms associated with GDF15.SOLUTION: The present invention includes anti- hGDF15 antibodies that bind to an epitope of hGDF15 comprising the amino acid sequence of DHCPLGPGRCCRLH (SEQ ID NO: 3) and uses thereof.SELECTED DRAWING: None

The invention relates to a small interfering RNA (Ribonucleic Acid) of a GDF15 gene, and a preparation method and application of the small interfering RNA. The small interfering RNA comprises a main body part and a modification part, the main body part contains a positive-sense strand and an antisense strand, the positive-sense strand is at least one nucleic acid sequence in SEQ ID NO.1-9, and the antisense strand is a corresponding accounting sequence of at least one of SEQ ID NO.1-9 '; the small interfering RNA of the GDF15 gene can cut and degrade mRNA of the GDF15 to mediate gene silencing, reverse a tumor immunosuppression microenvironment and recover the anti-tumor effect of immune cells, and a potential clinical scheme is provided for tumor treatment.

The present invention relates to the field of biotechnology, and more specifically, to an antibody against GDF15 or its use. The present invention provides a heavy-chain antibody that targets GDF15, which specifically binds to GDF15, inhibits the interaction between GDF15 and GFRAL, and can be used to treat diseases associated with GDF15 overexpression or to diagnose a patient's GDF15 level. The antibody provided by the present invention exhibits superior inhibitory activity against the binding of GDF15 to GFRAL compared to the positive control CTL002, superior specificity compared to the positive control PF-06946860, and superior hydrophilicity compared to the positive control PF-06946860.

The invention discloses application of a chemical small molecule CGI1746 in preparation of a preparation for treating obesity and related metabolic diseases, and relates to the technical field of small molecule drugs. The invention discloses a novel application of a chemical small molecule CGI1746 in preparation of a preparation for treating obesity and related metabolic diseases, and discloses a small molecule drug CGI1746 capable of promoting fat cell lipolysis, inhibiting fat cell differentiation, reducing lipid accumulation in liver cells and promoting expression of a cytokine GDF15. The polypeptide has the potential of being applied to relieving and preventing obesity and related metabolic diseases.

The present invention relates to GDF15 analogs and methods for reducing body weight and / or reducing food intake. In particular, the present invention relates to fusion proteins comprising a half-life prolonging protein, a linker and a GDF15 protein, which fusion proteins are useful as GDF15 agonists. These GDF15 agonists are useful for treating obesity, reducing body weight, reducing food intake, or reducing appetite.

The present application relates to the technical field of pathological evaluation, and particularly relates to a heat stroke myocardial injury mouse model construction and evaluation method, comprising constructing a heat stroke myocardial injury mouse model by increasing the core body temperature, determining the key time point of the intervention effect of different dose gradients of GDF15 after the heat stroke modeling; obtaining the cTn-I index and the ALT index based on the key time point, determining the injury type ratio based on the normalized values of the cTn-I index and the ALT index to determine the injury type of the heat stroke; adjusting the evaluation strategy in response to the injury type, obtaining the recovery rate of the cTn-I index and the ALT index of the model control group at each time point to determine the myocardial injury degree and the liver injury degree at the corresponding time point; obtaining the average recovery rate of the ALT of each dose group to determine the ALT recovery rate ratio between different dose groups, and adjusting the observation length of the dose group. The present application can distinguish the injury types by constructing the heat stroke myocardial injury model, and cannot adapt to the dynamic changes of different injury types.

The invention discloses a group of nucleic acid aptamers for specifically recognizing human pro-GDF15 as well as structural characteristics and application of the nucleic acid aptamers. The invention provides a nucleic acid aptamer. A consistent sequence of the nucleic acid aptamer is composed of GGWYTGC, N (3-6) and GGRYTGC. Wherein W is A or T, Y is C or T, R is A or G, N is A, T, C or G, and (3-6) represents 3, 4, 5 or 6 Ns. According to the present invention, the recombinant human GDF15 protein is adopted as the target spot, the SELEX technology is adopted to screen the group of the aptamers capable of specifically combining the monomer form pro-GDF15, and the aptamers can make up the existing antibody-based GDF15 detection technology, and can be used for distinguishing the precursor pro-GDF15 and the mature GDF15 molecule (homodimer) with different biological functions.

The present invention provides a GDF15-binding antibody or an antigen-binding fragment thereof. The antibody or the antigen-binding fragment thereof comprises: CDR sequences selected from at least one of the following or amino acid sequences having at least 66% identity with same: heavy chain variable region CDR sequences: SEQ ID NO: 1-34 and SEQ ID NO: 74-76; and light chain variable region CDR sequences: SEQ ID NO: 36-73 and SEQ ID NO: 77-82. According to embodiments of the present invention, the antibody or the antigen-binding fragment thereof can specifically bind to GDF15, can effectively block the binding of GFRAL and GDF15, and can also effectively inhibit Treg differentiation, and therefore can be used for preventing and / or treating cancers and cachexia.