41 results about "Proprotein convertase" patented technology

Described are RNAi agents, compositions that include RNAi agents, and methods for dual inhibition of an Apolipoprotein C-III (APOC3) and Proprotein Convertase Subtilisin Kexin 9 (PCSK9) gene. The APOC3-PCSK9 RNAi agents disclosed herein inhibit the expression of an APOC3 and a PCSK9 gene. Pharmaceutical compositions that include one or more APOC3-PCSK9 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described TSLP RNAi agents to hepatic cells, in vivo, provides for inhibition of APOC3 and / or PCSK9 gene expression, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including hypertriglyceridemia and hypercholesterolemia.

The invention relates to an shRNA (short hairpin Ribonucleic Acid) interference sequence of a targeted silence PCSK9 gene and a construction method and lipid-lowering application of a recombinant adeno-associated virus vector of the shRNA interference sequence. Hyperlipidaemia is a metabolic disease characterized by abnormal rising of cholesterol and triglyceride levels in blood, and the design of lipid-lowering drugs is the focus of attention to improvement of hyperlipidaemia. Proprotein convertase subtilisin / kexin type 9 (PCSK9) can be combined with a low-density lipoprotein receptor (LDL-R) and degrade the LDL-R, so that accumulation of LDL-C in blood is further promoted, and hyperlipidemia is caused. Aiming at the key target PCSK9, a specific shRNA interference sequence is designed, and a recombinant adeno-associated virus vector (rAAV) carrying the sequence is constructed by an enzyme digestion-connection method. In-vitro experiments prove that the vector can remarkably reduce the expression level of PCSK9 protein, so that the cyclic utilization of a low-density lipoprotein receptor (LDL-R) is promoted, and the concentration of low-density lipoprotein cholesterol (LDL-C) in plasma is reduced. The rAAV vector provided by the invention has the characteristics of low production cost, high transfection efficiency, lasting action time and the like, and provides a new thought for gene therapy of hyperlipidemia.

The present disclosure relates to small molecule inhibitors of proprotein convertase subtilisin-like / kexin type 9 (PCSK9), pharmaceutical compositions comprising said compounds, and their use in the prevention and treatment of diseases and disorders associated with PCSK9.

This invention provides an antigen-binding protein that binds to proprotein converterase subtilisin kexin type 9 (PCSK9), as well as a method for using and producing the antigen-binding protein. [Solution] The present invention provides an isolated neutralizing antigen-binding protein that interacts with proprotein converterase subtilisin kexin type 9 (PCSK9), and which contains a specific amino acid sequence that binds to the PCSK9 protein and reduces the LDLR-reducing effect of PCSK9 on LDLR.

This invention discloses the application of a polypeptide in inhibiting inflammatory pain, belonging to the field of biomedicine. The polypeptide is Mexneurin-3 (Mx-3), one of three Mexneurin polypeptides formed by the cleavage of ProMexneurin, a protein precursor found in the mammalian central nervous system, by proprotein convertase. This invention reveals that Mx-3, as an endogenous polypeptide, has significant analgesic effects, inhibiting both acute and chronic inflammatory pain with fewer side effects and greater safety. This invention also elucidates the analgesic mechanism of Mx-3, finding that it upregulates diacylglycerol (DAG) levels in the spinal cord and activates protein kinase C (PKC). The application of Mx-3 in inhibiting inflammatory pain provided by this invention can be used to develop safer and more effective novel analgesics, providing new ideas and references for the treatment of inflammatory pain.

The present disclosure provides pharmaceutical compositions comprising fibronectin based scaffold domain proteins that bind, for example, proprotein convertase subtilisin kexin-9 (PCSK9).

The present invention relates to methods of treating or preventing cholesterol related disorders, such as hypercholesterolemia, hyperlipidemia or dyslipidemia, using antibodies against proprotein convertase subtilisin / kexin type 9 (PCSK9). Formulations and methods of producing said formulations are also described.

The present invention relates to a dual-targeting siRNA agent comprising two distinct siRNAs targeting two different genes or their pharmaceutically acceptable salts, wherein the two distinct siRNAs or their salts are linked by a pharmaceutically acceptable ligand. The siRNA is a dsRNA composed of a sense strand and an antisense strand, and the two different genes are selected from a group consisting of angiotensinogen (AGT), proprotein convertase subtilisin / kexin type 9 (PCSK9), and human angiopoietin-like protein 3 (ANGPTL3). The present invention provides the application of the dual-targeting siRNA agent in the preparation of drugs for preventing or treating diseases associated with hypertension and / or dyslipidemia. The dual-targeting siRNA agent described in the present invention can effectively inhibit the expression of two target genes simultaneously in vivo, offering the advantages of strong non-antagonistic activity and high safety. The present invention also provides the siRNAs targeting corresponding genes for the aforementioned dual-targeting siRNA agent and their use for preventing or treating diseases associated with hypertension and / or dyslipidemia.

Method of lowering low-density lipoprotein cholesterol or preventing a cardiac event in a subject who has atherosclerotic cardiovascular disease or who is atherosclerotic cardiovascular disease risk equivalent, involving administering to the subject a prophylactically effective amount of an RNAi agent. Also, a method of preventing development of atherosclerotic cardiovascular disease in a subject involving administering to the subject a prophylactically effective amount of an RNAi agent. Further, a method of treating a subject who has atherosclerotic cardiovascular disease or who is atherosclerotic cardiovascular disease risk equivalent involving administering to the subject a therapeutically effective amount of an RNAi agent.

This invention provides the use of RNA interferants that inhibit PCSK9 synthesis in prophylactic or therapeutic methods. [Solution] A method for reducing low-density lipoprotein cholesterol or preventing cardiac events in a subject having atherosclerotic cardiovascular disease or being at equivalent risk to atherosclerotic cardiovascular disease, comprising the step of administering a prophylactic effective amount of RNAi to the subject. Also, a method for preventing the onset of atherosclerotic cardiovascular disease in a subject, comprising the step of administering a prophylactic effective amount of RNAi to the subject. Furthermore, a method for treating a subject having atherosclerotic cardiovascular disease or being at equivalent risk to atherosclerotic cardiovascular disease, comprising the step of administering a therapeutic effective amount of RNAi to the subject.

To provide an injection device for subcutaneous administration, for preventing cardiovascular events in a human subject.SOLUTION: The present invention provides an injection device for subcutaneous administration, comprising a fixed dose of 275 mg to 325 mg of an interfering ribonucleic acid (RNAi) agent. The device comprises a double-stranded ribonucleic acid comprising a sense strand and an antisense strand forming a double-stranded region, where the antisense strand comprises the nucleotide sequence of 5'-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3' (SEQ ID NO: 3), and the sense strand comprises the nucleotide sequence of 5'-csusagacCfuGfudTuugcuuuugu-3' (SEQ ID NO: 4), where a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C, or U; Af, Gf, Cf or Uf are 2'-fluoro A, G, C or U; dT is 2'-deoxythymidine; and s is a phosphorothioate linkage.SELECTED DRAWING: None

This provides a method to reduce cardiovascular risk in patients with a genetic profile associated with a response to proprotein converter subtilisin / kexin type 9 (PCSK9) inhibitor therapy. [Solution] A method for treating a patient at risk of major cardiovascular adverse events (MACE) includes: determining the patient's polygenetic risk score (CAD-PRS), which includes a weighted sum of multiple gene variants associated with coronary artery disease; identifying the patient as being at high risk of MACE if the patient has a CAD-PRS greater than a threshold CAD-PRS determined from a reference population; and administering a PCSK9 inhibitor to the patient if the patient has been identified as being at high risk of MACE.

Compositions and methods relating to ApoA-1 fusion polypeptides are disclosed. The fusion polypeptides include a first polypeptide segment corresponding to an ApoA-1 polypeptide or ApoA-1 mimetic, and may also include a dimerizing domain such as, e.g., an Fc region, which is typically linked carboxyl-terminal to the first polypeptide segment via a flexible linker. In some embodiments, the fusion polypeptide further includes a second polypeptide segment located carboxyl-terminal to the first polypeptide segment and which confers a second biological activity (e.g., an RNase, paraoxonase, platelet-activating factor acetylhydrolase, cholesterol ester transfer protein, lecithin-cholesterol acyltransferase, polypeptide that specifically binds to proprotein convertase subtilisin / kexin type 9, or polypeptide that specifically binds to amyloid beta). Also disclosed are dimeric proteins comprising first and second ApoA-1 fusion polypeptides as disclosed herein. The fusion polypeptides and dimeric proteins are useful in methods for therapy.

The invention relates to a dual-targeting siRNA agent, which comprises two different siRNAs targeting two different genes or pharmaceutically acceptable salts thereof, the two different siRNAs or salts thereof are connected through pharmaceutically acceptable ligands, the s-RNA is dsRNA composed of a sense strand and an antisense strand, and the s-RNA is dsRNA composed of a positive-sense strand and a negative-sense strand. The two different genes are selected from two of angiotensinogen (AGT), proprotein convertase subtilisin 9 (PCSK9) and human angiopoietin-like protein 3 (ANGPTL3). The invention provides application of the dual-targeting s iRNA agent in preparation of drugs for preventing or treating diseases related to hypertension or / and lipid disorder. The dual-targeting siRNA agent can effectively inhibit expression of two target genes in vivo at the same time, and has the advantages of being high in mutual non-antagonistic activity and high in safety. The invention also provides the s iRNA of the corresponding gene of the dual-targeting s iRNA agent and application of the s iRNA to prevention or treatment of diseases related to hypertension or / and lipid disorder.

This invention relates to compounds of Formula I and their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs. The compounds of Formula I can be used as inhibitors of proprotein convertase subtilisin 9 (PCSK9), effectively inhibiting PCSK9 activity and reducing the concentration of low-density lipoprotein cholesterol in plasma, and have good application prospects in the preparation of drugs for the treatment or prevention of cardiovascular diseases.

Disclosed herein is a wearable drug delivery device including a container filled at least partially with a drug including at least one of a PCSK9 (Proprotein Convertase Subtilisin / Kexin Type 9) specific antibody, a granulocyte colony-stimulating factor (G-CSF), a sclerostin antibody, or a calcitonin gene-related peptide (CGRP) antibody. The wearable drug delivery device may include a needle and an insertion mechanism configured to insert the needle into a patient. A fluid pathway connector may define a sterile fluid flowpath between the container and the insertion mechanism. Optionally, a cannula initially disposed about the needle may be included. The cannula may be retained in the patient at an injection site created by the needle after the needle is withdrawn from the patient. Methods of assembly and operation are also provided.

A low-molecular weight compound having an activity of inhibiting the functions of proprotein convertase subtilisin / kexin type 9 (PCSK9), a PCSK9 inhibitor containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as an active component, and a medicament containing the PCSK9 inhibitor as an active component for use in prevention or treatment of one or more symptoms, diseases, or disorders, related to the functions of PCSK9.

The present invention relates to methods of treating or preventing cholesterol related disorders, such as hypercholesterolemia, hyperlipidemia or dyslipidemia, using antibodies against proprotein convertase subtilisin / kexin type 9 (PCSK9). Formulations and methods of producing said formulations are also described.

An siRNA which inhibits proprotein convertase subtilisin / kexin type 9 (PCSK9) gene expression, a pharmaceutical composition containing the siRNA, and a conjugate. Each nucleotide in the siRNA is independently a modified or unmodified nucleotide. The siRNA contains a sense strand and an antisense strand. The sense strand contains nucleotide sequence I; nucleotide sequence I having the same length as the nucleotide sequence shown in SEQ ID NO: 1, with no more than three nucleotides differences. The antisense strand contains nucleotide sequence II, nucleotide sequence II having the same length as the nucleotide sequence shown in SEQ ID NO: 2, with no more than three nucleotides differences. The siRNA, pharmaceutical composition thereof and the conjugate can effectively treat and / or prevent hypercholesterolemia.

The invention discloses an application of polypeptide in preparation of antidepressant drugs, and belongs to the field of biological medicine, the polypeptide is neuropeptide PEN or a functional fragment and a derivative thereof, and the PEN is one of a plurality of derivative peptides formed by cutting a protein precursor proSAAS existing in a central nervous system of a mammal through proprotein convertase. Research finds that PEN as an endogenous polypeptide can significantly shorten the immobility time of a mouse in a tail suspension experiment and a forced swimming experiment and improve the depression-like behavior of the mouse, shows an obvious anti-depression effect, and has no obvious influence on the movement function of the mouse. A further research result shows that the anti-depression mechanism of PEN is related to inhibition of NMDAR2B / CaMKII signals of a mouse hippocampus and increase of ERK1 / 2 protein activity of the hippocampus. The invention discovers potential application of PEN in preparation of antidepressant drugs for the first time, and provides a new target and theoretical basis for development of novel, safe and effective antidepressant drugs.

The present disclosure relates to an RNAi composition for inhibiting expression of proprotein convertase subtilisin kexin 9 (PCSK9) and an application thereof. The RNAi composition can be used for treating and / or preventing PCSK9 related diseases or symptoms such as hyperlipidemia, cardiovascular diseases and the like.

An siRNA which inhibits proprotein convertase subtilisin / kexin type 9 (PCSK9) gene expression, a pharmaceutical composition containing the siRNA, and a conjugate. Each nucleotide in the siRNA is independently a modified or unmodified nucleotide. The siRNA contains a sense strand and an antisense strand. The sense strand contains nucleotide sequence I; nucleotide sequence I having the same length as the nucleotide sequence shown in SEQ ID NO: 1, with no more than three nucleotides differences. The antisense strand contains nucleotide sequence II, nucleotide sequence II having the same length as the nucleotide sequence shown in SEQ ID NO: 2, with no more than three nucleotides differences. The siRNA, pharmaceutical composition thereof and the conjugate can effectively treat and / or prevent hypercholesterolemia.

Provided herein are gene repressor systems comprising fusion proteins, such as fusion proteins comprising a DNA binding domain such as a TALE, zinc finger or catalytically-dead CRISPR protein and guide nucleic acid (gRNA), which are useful in the repression of a proprotein convertase subtilisin / kexin Type 9 (PCSK9) gene. Also provided are methods of using such systems to repress transcription of PCSK9.

The application discloses a polynucleotide sequence for simultaneously reducing blood fat and blood pressure and application thereof. Cell and mouse experiments show that the application can significantly inhibit the expression levels of multiple blood fat and blood pressure molecular targets such as proprotein convertase subtilisin / kexin type 9 (PCSK9), angiotensinogen (AGT) and beta-hydroxy-beta-methylglutaryl-coenzyme a reductase (HMGCR), thereby reducing the blood fat and blood pressure levels of a related disease model mouse. The application is expected to be applied to treating related cardiovascular and cerebrovascular diseases complicated with high blood fat and high blood pressure symptoms.

Aspects of the technology relate to a composition comprising: (i) a first RNAi agent that targets Proprotein convertase subtilisin / kexin type 9 (PCSK9) and a second RNAi agent that targets angiotensinogen (AGT); (ii) a first RNAi agent that targets PCSK9 and a third RNAi agent that targets Apolipoprotein A (LPA); (iii) a second RNAi agent that targets AGT and a third RNAI agent that targets LPA, or (iv) a first RNAi agent that targets PCSK9, a second RNAi agent that targets AGT, and the third RNAi agent that targets LPA.

The present invention relates to oligomeric compounds and conjugates thereof that target Proprotein Convertase Subtilisin / Kexin type 9 (PCSK9) PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for a range of medical disorders, such as hypercholesterolemia and related disorders.

To provide an in vitro method for assessing the risk of developing sepsis, systemic inflammatory response syndrome (SIRS), septic shock, or multiple organ dysfunction syndrome (MODS) in a subject. Also provided are pharmaceutical compositions for the treatment of sepsis, SIRS, septic shock or MODS in a subject.SOLUTION: Determining or having determined the presence or absence of i) a PCSK9 variant nucleic acid sequence encoding a Pro-protein convertase subtilisin / kexin type 9 (Arg46Leu) PCSK9; and ii) a low-density-lipoprotein receptor (LDLR) variant nucleic acid sequence comprising a single nucleotide polymorphism rs6511720 in a biological sample obtained from the subject, wherein the subject is a PCSK9 reference and being a LDLR reference indicates that the subject has an increased risk of developing SIRS / MODS.SELECTED DRAWING: None

Compositions and methods relating to ApoA-1 fusion polypeptides are disclosed. The fusion polypeptides include a first polypeptide segment corresponding to an ApoA-1 polypeptide or ApoA-1 mimetic, and may also include a dimerizing domain such as, e.g., an Fc region, which is typically linked carboxyl-terminal to the first polypeptide segment via a flexible linker. In some embodiments, the fusion polypeptide further includes a second polypeptide segment located carboxyl-terminal to the first polypeptide segment and which confers a second biological activity (e.g., an RNase, paraoxonase, platelet-activating factor acetylhydrolase, cholesterol ester transfer protein, lecithin-cholesterol acyltransferase, polypeptide that specifically binds to proprotein convertase subtilisin / kexin type 9, or polypeptide that specifically binds to amyloid beta). Also disclosed are dimeric proteins comprising first and second ApoA-1 fusion polypeptides as disclosed herein. The fusion polypeptides and dimeric proteins are useful in methods for therapy.