105 results about "PCSK9" patented technology

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.

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]

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 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.

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.

This invention discloses a circular RNA agent targeting PCSK9 and its applications, relating to the field of biomedical technology. The circular RNA agent is a single-stranded closed-circular oligonucleotide containing an antisense sequence complementary to the transcription of the PCSK9 gene. It lacks free 5' and 3' ends, and does not contain overhangs, hairpin structures, or double-stranded regions. The molecules are linked by 3'-5' phosphodiester bonds. This circular RNA agent can be modified with GalNAc or prepared into pharmaceutical compositions for the treatment of diseases or conditions related to abnormal PCSK9 gene expression or activity. The circular RNA agent provided by this invention exhibits high stability, a long half-life, low immunogenicity, low modification toxicity, and high target gene inhibitory activity. It can significantly prolong the dosing interval, improve patient compliance, and provide a safer, longer-acting drug option for lipid-lowering therapy.

A dual component system for treating a genetic disorder is provided. The system includes (a) a gene editing vector comprising an expression cassette comprising a nucleic acid sequence encoding a nuclease and regulatory sequences that direct expression of the nuclease in a target cell comprising a PCSK9 gene; and (b) a donor vector comprising a nucleic acid sequence encoding an exogenous product for expression from the PCSK9 locus, wherein the inserted nucleic acid sequence does not encode PCSK9, wherein the system further comprises sequences that direct the nuclease to specifically targets the native PCSK9 gene locus; and wherein the native PCSK9 in the target cell is optionally ablated or reduced post-dosing with the dual component system.

The invention belongs to the technical field of medicinal chemistry, and discloses a heterocyclic derivative inhibitor and application thereof. The invention provides a compound with a structure as shown in a formula I or pharmaceutically acceptable salt thereof, and the compound in the formula I has relatively strong PCSK9 inhibitory activity, shows excellent oral pharmacokinetic characteristics in vivo, and can be used for treating and / or preventing cardiovascular and cerebrovascular diseases.

A method for preparing enhanced CAR-T-cells based on interfering or knocking out the human PCSK9 gene and an application thereof are provided. The method includes performing the RNA interference (RNAi) for the human PCSK9 gene by the artificial microRNA (miRNA) to prepare the enhanced CAR-T or preparing the enhanced CAR-T by CRISPR-Cas9 gene-editing technology by using sgRNA to knock out the human PCSK9 gene. The method uses PCSK9 gene knockdown element or CRISPR / Cas9 technology to specifically knock down or knock out the expression of PCSK9 in CAR-T-cells, which effectively enhances the therapeutic effect of CAR-T-cells on malignant solid tumors, and can enhance the tumor therapeutic effect of immune checkpoint blockade therapy.

This invention relates to the field of gene editing technology, and in particular to an sgRNA, a gene editing system, and their uses. The sgRNA comprises a target sequence targeting the PCSK9 gene or a target sequence targeting the APOC3 gene. The nucleotide sequence encoding the target sequence targeting the PCSK9 gene comprises a sequence as shown in any one of SEQ ID Nos. 1-22; the nucleotide sequence encoding the target sequence targeting the APOC3 gene comprises a sequence as shown in any one of SEQ ID Nos. 23-36. Through systematic screening and experimental verification, this invention has obtained sgRNAs capable of efficiently and specifically targeting both the PCSK9 and APOC3 genes. Based on the screened sgRNAs, this invention has developed a dual-target gene editing system capable of simultaneously targeting both the PCSK9 and APOC3 genes. This provides a reliable core component for developing gene-editing-based therapies for lipid metabolism diseases, and has significant clinical significance and application prospects.

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.

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.

Disclosed are, inter alia, combinations comprising a first antisense (e.g., first double stranded RNAi (dsRNAi)) agent for inhibiting expression of proprotein convertase subtilisin kexin 9 (PCSK9), for example, human PCSK9, and a second antisense agent (e.g., second dsRNAi agent) for inhibiting expression of lipoprotein (a) (Lp(a)); pharmaceutical compositions including the same, and methods of treatment using the same.

The application discloses application of ac4C modification of NAT10 and PCSK9 mRNA in diagnosis and treatment of DAVD, and belongs to the technical field of biological medicine. The application finds that NAT10 increases expression of PCSK9 by ac4C modification of PCSK9 mRNA, thereby promoting occurrence and development of degenerative aortic valve disease; by inhibiting expression of NAT10 to reduce the ac4C modification level of PCSK9 mRNA, osteogenic differentiation of hVICs can be effectively inhibited, and valve calcification can be delayed or inhibited. Therefore, the application proposes to jointly detect the ac4C modification levels of NAT10 and PCSK9 mRNA, which can be used for diagnosis of DAVD; and the ac4C modification of NAT10 and PCSK9 mRNA can be jointly targeted to prepare or screen drugs for treating DAVD. The application provides a new action target for precise diagnosis of DAVD and development of a targeted drug.

The invention relates to the technical field of animal models, and particularly discloses a construction method and application of a mouse model with fat dystrophy complicated with atherosclerosis, and the construction method comprises the following steps: mating MED1flox / flox mice with Adipoq-CreERT2 mice to obtain F1-generation mice; the F1-generation mice and MED1flox / flox mice are subjected to backcross, the mice with the genotype being MED1fl / flAdipoq-Cre < + / -> are screened, tamoxifen is injected to induce fat cell specific Cre recombinase expression, and fat cell specific MED1 gene knockout mice are obtained; and performing caudal vein injection of AAV8-PCSK9 virus and feeding with a high-cholesterol and high-fat feed to obtain the fat dystrophy complicated with atherosclerosis mouse model. According to the method provided by the invention, the mouse model with fat dystrophy complicated with atherosclerosis is successfully constructed and obtained, and collaborative simulation and regulation of phenotypes of two diseases are realized.

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

The invention belongs to the field of biological medicine, and relates to siRNA, a conjugate thereof and application of the siRNA and the conjugate in related diseases such as blood fat. The siRNA comprises a positive-sense strand and an antisense strand, the positive-sense strand comprises a nucleotide sequence I, and the antisense strand comprises a nucleotide sequence II; each nucleotide in the nucleotide sequence I and the nucleotide sequence II is modified or unmodified nucleotide; the nucleotide sequence I and the nucleotide sequence II are at least partially reversely complementary to form a double-stranded region; the nucleotide sequence I is basically consistent with the first nucleotide sequence, and the first nucleotide sequence is a nucleotide sequence with the length of at least 19 nucleotides in mRNA expressed by the PCSK9 gene. According to the present invention, the siRNA and the conjugate thereof can specifically target the liver, can be complementarily paired with the liver PCSK9 mRNA sequence, and can induce the PCSK9 mRNA degradation, such that the synthesis of the PCSK9 in the liver can be inhibited, the PCSK9 serum level can be durably and significantly reduced, and the related diseases caused by excessive PCSK9 can be effectively prevented and / or treated.