239 results about "PCSK9" patented technology

The present invention discloses a pharmaceutical composition comprising a circular RNA and a drug delivery carrier. Compared with traditional linear 1 * siRNA and annular 1 * siRNA, the number of repeated series connection of positive-sense strands is increased to include but not limited to two or more, it is accidentally found that the silence effect is remarkably enhanced, the expression level of the PCSK9 gene can be remarkably reduced, and degradation of mRNA of PCSK9 protein is mediated. The nano-particles are used for delivering oligonucleotide, so that the stability is improved, the immunogenicity is reduced, the effects of lowering cholesterol, reducing aortic plaque load and resisting atherosclerosis are improved, and the nano-particles are safe and free of obvious liver and kidney toxicity and have a wide application prospect in the aspect of preparing medicines for treating hypercholesterolemia and coronary heart disease.

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.

Relating to the technical field of gene therapy, provided is an siRNA molecule for inhibiting PCSK9 expression, and use thereof. Particularly, an siRNA molecule for inhibiting PCSK9 expression (comprising a sense strand and an anti-sense strand that are complementary to form a double-stranded region) and a pharmaceutical composition comprising the same are disclosed. The siRNA molecule has a high silencing efficiency and a long-lasting silencing effect for PCSK9 gene, and is useful in the manufacture of products for inhibiting PCSK9 protein expression, products for reducing the concentration of low-density lipoprotein or low-density lipoprotein cholesterol in serum; and products for relieving the symptoms of PCSK9 gene-mediated diseases.

The invention provides annular multi-tandem PCSK9 siRNA, which comprises at least one positive-sense strand sequence and at least one spacer sequence. The sense strand of the cyclic siRNA is derived from an engineered parent DNA template containing all essential sequences, comprising in the following order a first cyclization element, optionally at least one first restriction enzyme recognition sequence, at least one target sequence, optionally at least one second restriction enzyme recognition sequence, and a second cyclization element. The annular multi-tandem RNA positive-sense strand can combine and deliver a plurality of antisense strand RNAs, and the combination of the positive-sense strand and the antisense strand is increased while the stability advantage of the annular RNA is utilized.

A nucleic acid molecule comprising: i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a nucleotide sequence comprising a cardiovascular disease associated gene to be silenced and wherein said cardiovascular gene is proprotein convertase subtilisin kexin 9 (PCSK9) there is provided a single stranded deoxyribonucleic acid (DNA) molecule conjugated to the 5’ end of said sense strand; and ii) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a different cardiovascular disease associated gene to be silenced wherein said cardiovascular gene is lipoprotein (a) (Lp(a)) and wherein there is provided a single stranded deoxyribonucleic acid (DNA) molecule conjugated to the 5’ end of said sense strand wherein the single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules.

Provided is a pharmaceutical composition, comprising a circular RNA and a drug delivery carrier. It is surprisingly found that compared with conventional linear 1 x siRNAs and circular 1 x siRNAs, increasing the number of tandem repeats in the sense strand to two or more significantly enhances the silencing effect, significantly reduces the expression level of the PCSK9 gene, and mediates the degradation of the PCSK9 protein mRNA. The use of nano-particles for delivering oligonucleotides features improved stability, reduced immunogenicity, improved cholesterol-lowering, aortic plaque load-reducing and anti-atherosclerotic effects, good safety, no significant liver and kidney toxicity, and therefore good prospects in preparing medicaments for treating hypercholesterolemia and a coronary heart disease.

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.

Provided is a circular concatemeric PCSK9 siRNA, comprising at least one sense strand sequence and at least one spacer sequence. The sense strand of the circular siRNA is derived from an engineered parental DNA template containing all essential sequences, which comprises, in the following order: a first cyclization element, optionally at least one first restriction enzyme recognition sequence, at least one target sequence, optionally at least one second restriction enzyme recognition sequence, and a second cyclization element. The sense strand of the circular concatemeric RNA can bind and deliver a plurality of antisense strand RNAs, enhancing the binding between the sense and antisense strands while leveraging the stability advantage of the circular RNA.

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 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 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 present invention relates to methods for treating diseases or conditions in which proprotein convertase subtilisin / kexin type 9 (PCSK9) expression or activity causes an impact by administration of PCSK9-specific antibodies or antigen-binding fragments thereof and preferably by additional administration of an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-COA reductase). The present invention further relates to PCSK9-specific antibodies or antigen-binding fragments thereof for use in the treatment of diseases or conditions in which PCSK9 expression or activity causes an impact.The present invention also relates to articles of manufacture comprising packaging material, PCSK9-specific antibodies or antigen-binding fragments thereof, and a label or packaging insert indicating which groups of patients can be treated with said antibodies or fragments, which groups of patients must not be treated with said antibodies or fragments, and which dosage regimen should be used.The present invention further relates to methods of testing the efficacy of PCSK9-specific antibodies or antigen-binding fragments thereof for the treatment of certain diseases or conditions and for the treatment of specific sub-groups of patients.

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. Further provided herein are compositions and methods of treating conditions related to coronary disease.

The present disclosure provides pharmaceutic compositions for oral delivery comprising an antisense oligonucleotide (e.g., CIVI 008) and an oral delivery agent such as 5-CNAC. In some aspects, the disclosure provides a capsule comprising a dry blend of CIVI 008 and 5-CNAC, and optionally a statin.

The invention provides application of an ENO1K71R mutant as a target spot in screening preparations for regulating and controlling glycolysis of colon cancer cells and improving tumor microenvironment, and belongs to the technical field of biological medicine and molecular biology. The research on the colon cancer cells which stably knock down PCSK9 finds that PCSK9 achieves the regulation effect on lactic acid metabolism in the colon cancer cells by regulating ENO1 lactic acid modification, the blank of ENO1 protein lactic acid modification and the regulation effect of the ENO1 protein lactic acid modification in tumor progression is filled, a lactic acid modification site is verified by constructing an ENO1K71R mutation experience, and the result shows that the PCSK9 can be used for regulating the lactic acid metabolism in the colon cancer cells. After ENO1 (K71) point mutation, ENO1 lactic acid can be inhibited, a new site is provided for ENO1 lactic acid modification, and a theoretical basis is also provided for developing novel tumor targeted drugs.

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 discloses a composition with effects of losing weight and reducing blood fat. Every 100g of the composition comprises the following components and contents: (1) 10-30mg of adiponectin functional fragments; (2) 5 to 15 mg of PCSK9 inhibitory peptide; (3) 1-5 g of a radix puerariae extract; (4) 1-3 g of garcinia cambogia extract; (5) 0.5-2 g of a green coffee bean extract; (6) 1 to 3g of microencapsulated fish oil; (7) 0.5 to 1g of chitosan; and 5 to 10 g of erythritol. Through the synergistic effect of various bioactive components, the composition can effectively reduce fat accumulation and reduce the blood fat level, and meanwhile has good taste and use convenience. The composition disclosed by the invention provides an innovative solution for losing weight and reducing blood fat, and has potential clinical and commercial application values.

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.

A dual vector system for treating ornithine transcarbamylase deficiency is provided. The system includes ((a) a gene editing AAV comprising a first AAV rh79 capsid and a first vector genome comprising a 5′ ITR, a sequence encoding a meganuclease that targets PCSK9 under control of regulatory sequences that direct expression of the meganuclease in a target cell comprising a PCSK9 gene, and a 3′ ITR; and(b) a donor AAV vector comprising a second AAV capsid and a second AAV rh79 vector genome comprising: a 5′ITR, a 5′ homology directed recombination (HDR) arm, a transgene encoding ornithine transcarbamylase (OTC) and regulatory sequences that direct expression of the transgene in the target cell, a 3′ HDR arm, and a 3′ ITR.

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 prevention and treatment of diseases and conditions associated with PCSK9.

The disclosure relates to inhibitors of PCSK9 useful in the treatment of lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I):or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein R1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are described herein.

The invention belongs to the technical field of biological medicine, and particularly relates to an integrated PCSK9 adenine base editing system and application. The integrated PCSK9 adenine base editing system comprises the following structures: (1) a single plasmid; (2) a PCSK9 adenine base editor; and (3) delivering the carrier. Wherein the single plasmid and the PCSK9 adenine base editor form a single plasmid integrated adenine base editor, and then the single plasmid integrated adenine base editor is wrapped by the delivery carrier to form the integrated PCSK9 adenine base editing system. The invention provides an integrated base editing system with a built-in liver specific promoter, the integrated base editing system can be specifically expressed in liver cells, and meanwhile, the problems that double-stranded DNA needs to be cut off in a traditional Crispr / gRNA technology, and the off-target effect and uncertainty of gene editing are greatly relieved are solved; in addition, the problems that in a traditional double-plasmid system, the efficiency of two plasmids entering the same target cell is different, and the editing efficiency is low can be solved.

Provided are a small interfering RNA (siRNA) for inhibiting expression of proprotein convertase subtilisin / kexin type 9 (PCSK9) in a cell, a vector and a cell comprising a nucleotide encoding the same, and a method for treating a disease or symptom associated with PCSK9 expression in a subject using the siRNA, the vector or the cell.

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.