148 results about "PCSK9" 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 present invention discloses an interfering RNA for inhibiting PCSK9 gene and use thereof. The interfering RNA comprises a nucleotide sequence set forth in any one or two or more of SEQ ID NOs: 1-40, 73-96. The interfering RNA of the present invention can better target and silence hepatic PCSK9 mRNA, reduce the protein level of PCSK9, enhance LDL-C metabolism, and reduce serum cholesterol, providing a solid technical foundation for the development of siRNA medicaments for the prevention, treatment, and symptom alleviation of PCSK9 gene-mediated diseases.

A pharmaceutical composition comprising a first RNAi agent and a second RNAi agent, the first RNAi agent comprising one or more first and / or one or more first siRNA conjugates capable of inhibiting APOC3 mRNA; a second RNAi agent comprising one or more second siRNAs and / or one or more second siRNA conjugates capable of inhibiting PCSK9 mRNA; the weight ratio of the first RNAi agent to the second RNAi agent in the pharmaceutical composition is (10: 1)-(1: 10) based on the total amount of the siRNA and the siRNA group. The pharmaceutical composition and the treatment method can effectively treat and / or prevent diseases or symptoms related to hyperlipidemia.

The invention discloses an interfering RNA (Ribonucleic Acid) for inhibiting a PCSK9 gene and application of the interfering RNA. The interfering RNA comprises any one or more than two nucleotide sequences as shown in SEQ ID NO: 1-40 and SEQ ID NO: 73-96. The interfering RNA can better target and silence mRNA of the liver PCSK9, reduce the protein level of the PCSK9, enhance LDL-C metabolism and reduce serum cholesterol, and a solid technical basis is provided for research and development of siRNA drugs for prevention and treatment of PCSK9 gene mediated diseases and symptom relief.

The invention relates to a method for semi-solid-phase synthesis of a polycyclic compound and an intermediate, a long chain is synthesized through solid phase, then two-step ring closing is performed to form a key intermediate, and simple derivation is performed on the basis of the key intermediate to obtain a PCSK9 antagonist compound. According to the invention, starting materials for solid-phase synthesis are selected, steric hindrance is effectively avoided, and solid-phase reaction and subsequent liquid-phase correlation cyclization can be smoothly carried out, so that the yield is improved, and the cost is reduced.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents such as small interfering RNA (siRNA) molecules, able to inhibit proprotein convertase subtilisin kexin 9 (PCSK9) gene expression. Also disclosed are pharmaceutical compositions that include PCSK9 RNAi agents and methods of use thereof. The PCSK9 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosamine, to facilitate the delivery to hepatocyte cells. Delivery of the PCSK9 RNAi agents in vivo provides for in vivo provides for inhibition of PCSK9 gene expression and thereby reduction of PCSK9 protein. The RNAi agents can be used in methods of treatment of diseases or disorders mediated at least in part by PCSK9 gene expression, including among others hypercholesterolemia, familial hypercholesterolemia including heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH), familial hypobetalipoproteinemia, hyperlipidemia, coronary artery disease, polygenic dyslipidemia, heart disease, cardiovascular disease (CVD) including clinical atherosclerotic cardiovascular disease (ASCVD).

Provided is an RNA inhibitor inhibiting PCSK9 gene expression, comprising an antisense strand, the antisense strand comprising a complementary region complementary to at least a portion of mRNA encoding PCSK9, and the length of the complementary region being 17-23 nucleotides; the antisense strand comprises any one of the following nucleotide sequences: SEQ ID NO.: 328-654, 1045-1107, 1125-1146 or 1149-1170, or a sequence differing therefrom by no more than 3 nucleotides. Also provided is a pharmaceutical composition, comprising the described RNA inhibitor inhibiting PCSK9 gene expression, and further comprising a delivery medium, and / or a pharmaceutically acceptable excipient and / or carrier and / or diluent.

The invention relates to a synthesis method of a polycyclic compound and an intermediate, a long chain is synthesized firstly, then two-step ring closing is performed to form a key intermediate, and simple derivation is performed on the basis of the key intermediate to obtain a PCSK9 antagonist compound. According to the invention, a ring closing route and an intermediate are optimized, and the ring closing yield is improved.

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 invention relates to a stable formulation containing a high concentration of an anti-PCSK9 antibody. The formulation comprises a therapeutically effective dose of an anti-PCSK9 antibody or an antigen-binding fragment thereof, a pharmaceutically acceptable buffer, an osmotic pressure regulator, and / or a surfactant, and exhibits long-term stability. When the formulation is a liquid formulation or a reconstituted liquid formulation of a lyophilized formulation, it exhibits low viscosity and long-term stability. The present invention also provides a method for preparing the formulation and its use in preparing a medicament for treating, preventing, and / or ameliorating any disease or symptom associated with PCSK9.

Provided herein are compositions, methods of making the same, and methods for targeted delivery of therapeutic agents for modifying expression and function of target genes, e.g. proteins involved in lipid and cholesterol metabolism such as PCSK9.

The present invention belongs to the field of drug synthesis, and specifically relates to a heterocyclic derivative inhibitor, and the preparation thereof and the use thereof. Disclosed in the present invention is a compound having a structure as represented by formula I, or an isomer or pharmaceutically acceptable salt thereof. The compound of formula I provided by the present invention has strong PCSK9 inhibitory activity, and can be used for treating and / or preventing cardiovascular and cerebrovascular diseases.

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.

The invention relates to the technical field of biological medicine. The invention provides a PCSK9-targeted PROTAC oral drug as well as a preparation method and application thereof. The drug comprises the following structures: a PCSK9 binding peptide, an E3 ubiquitin ligase ligand, a cell penetrating peptide and a flexible linker. The medicine provided by the invention can be used for preparing products for treating lipid metabolism disorder diseases such as hypercholesteremia and atherosclerosis. In addition, the medicine disclosed by the invention can also be combined with statins to synergistically enhance the lipid-lowering curative effect.

The present disclosure relates to siRNA and its use for targeting control of PCSK9 gene expression.Experimental results show that oligonucleotide sequences with some alternating modifications and specific template modifications can significantly inhibit PCSK9 expression, and can be used to develop drugs for the treatment of PCSK9-related diseases.

Disclosed are compounds of Formula I or salts thereof, wherein A, B, D, X, R1, R2, and R8 are as defined herein, and wherein the compounds have PCSK9 antagonistic properties. Also described are pharmaceutical formulations comprising the compounds of Formula I or salts thereof, and methods for treating cardiovascular diseases and conditions associated with PCSK9 activity, such as atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular diseases and cardiometabolic conditions. #imgabs0#

The application discloses a method for rapidly and quantitatively determining biological activity of anti-PCSK9 monoclonal antibody drugs, and is based on HepG2 liver cancer cells, and utilizes the principle that specific binding of a series of concentration gradient PCSK9 monoclonal antibodies to a certain concentration of PCSK9 protein indirectly causes a dose response of DiI-LDL absorption to LDL receptors on the surface of liver cells, so that a biological activity detection method of the PCSK9 monoclonal antibody drugs is preliminarily established, and methodological verification proves that the method has strong specificity, good accuracy and high precision, and can be used for release detection of products, and has important significance for process control in a production process and drug quality control.

The invention discloses a marker combination for diagnosing heart failure blood stasis syndrome and application thereof, the marker combination comprises a marker A and a marker B, the marker A is Cr, and the marker B is selected from at least one of PCSK9, AFM and APOC1. The marker combination provided by the invention is applied to clinical diagnosis or auxiliary diagnosis of heart failure blood stasis syndrome patients, has relatively high sensitivity and specificity, and can effectively distinguish the heart failure blood stasis syndrome patients from heart failure non-blood-stasis syndrome patients; reliable basis and practical guidance can be provided for clinical diagnosis and drug treatment of the heart failure blood stasis syndrome, and the accuracy and standardization degree of traditional Chinese medicine syndrome differentiation diagnosis can be improved.

A chemically modified polynucleotide encoding a fusion protein, wherein the chemically modified polynucleotide comprises a sequence of SEQ ID NO: 701 is claimed wherein the fusion comprises a Cas9 nickase and and deaminase, such as an adenosine deamnase TadA. and which further comprises a protospacer found on a gene encoding Angiopoietin-like 3 protein (ANGPTL3). The chemical modifications may include phosphorothioate linkages and 2'-O-methyl modfied nucleosides. Use of such fusions in treating cardiovascular conditions is further claimed. [Figure 3]

Disclosed are compounds of Formula I: wherein A, B, D, X, R1, R2 and R8 are as defined herein, or salts thereof, which have the properties of antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I, or salts thereof, and methods of treating cardiovascular diseases and conditions associated with PCSK9 activity, such as atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or associated cardiovascular diseases and cardiovascular metabolic conditions.

The application belongs to the field of biological medicine, and particularly relates to an RNAi reagent targeting PCSK9 and use. The application significantly improves the inhibition effect of the RNAi reagent on PCSK9 by improving a modification mode, and thus has better application potential in preventing or treating diseases related to PCSK9.

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

The invention relates to a siRNA for targeted regulation of PCSK9 gene expression and a use thereof. Experimental results show that some oligonucleotide sequences subject to alternate modification and specific template modification can significantly inhibit PCSK9 expression, and can be used for developing a drug for treating PCSK9-related diseases.

The invention belongs to the field of nucleic acid editing, and particularly relates to the technical field of regularly clustered interval short palindromic repeat (CRISPR). Specifically, Cas9 or smaller Cas-SF01 (a Cas12i3 variant) is utilized to reasonably design and construct a compact mRNA-delivered epigenetic suppressor in an engineering manner, and an optimized mRNA structure, lipid nanoparticle (LNP) delivery, OFF-E-V2 mRNA optimized by single intravenous injection and selected guide RNA (gRNA) targeting mouse PCSK9 are combined, so that circulating PCSK9 protein is reduced by about 90%, corresponding LDL-C level is reduced by about 55%, and the PCSK9 protein is reduced by about 90%. The effect lasts for at least 180 days. Compared with a corresponding object based on Cas9, an editor based on Cas-SF01 shows higher specificity, and off-target methylation events are fewer. The optimized LNP formulations also exhibit good safety. These findings establish a powerful and versatile platform for promoting a transient delivery-based engineered mRNA editor to achieve precise and lasting epigenetic silencing in vivo therapy.

The application discloses application of a genipin in preparation of a medicine for treating cholangiocarcinoma, and belongs to the field of biological medicines. The cell experiment result shows that the genipin can inhibit cholangiocarcinoma cell proliferation, migration and invasion capacity. The application proves that the genipin can effectively relieve occurrence and development of cholangiocarcinoma by constructing an in-situ cholangiocarcinoma animal model, observing mouse liver weight and liver coefficient, and observing liver tissue pathological HE staining. The application also verifies that the genipin can directly combine with PCSK9 by using proteomics, Western blot, molecular docking technology, surface plasmon resonance experiment and detection of cholesterol and lipid raft level, promotes accumulation of free cholesterol in tumor cells, disturbs cholesterol homeostasis and changes lipid raft structure, thereby playing an anti-tumor role. The application first finds that the genipin has specific effects in inhibiting cholangiocarcinoma progression, and is non-toxic and has no side effects, and can be used alone or in combination as a means for preventing and treating cholangiocarcinoma for development.

Disclosed herein are methods of disease treatments by administering to a subject in need thereof a pharmaceutical composition comprising gene editing compositions. The methods disclosed herein can provide durable in vivo editing of PCSK9. More particularly, the compositions disclosed herein are capable of in vivo editing PCSK9 gene in humans and reducing PCSK9 protein and LDL-C for a potentially transformative treatment of cardiovascular disease, the leading cause of death in the United States and world-wide. Various aspects of the compositions, use and preparation are disclosed, including clinically supported therapeutically effective and safe human dosing of the compositions.