CN114432447A - Application of PCSK9 inhibitor in preparation of medicine for treating pulmonary fibrosis - Google Patents
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Abstract
The invention belongs to the technical field of medical biology, and particularly relates to an effect of proprotein convertase Bacillus subtilis convertase (PCSK 9) in a pulmonary fibrosis pathogenesis, and an application of a PCSK9 inhibitor in preparation of a drug for treating pulmonary fibrosis. The application of the PCSK9 inhibitor which is a PCSK9 small molecule compound, or a PCSK9 interference RNA, or a PCSK9 monoclonal antibody, or a PCSK9 mimic polypeptide, or a PCSK9 mimic antibody protein, or a PCSK9 antisense oligonucleotide, or a PCSK9 vaccine in the preparation of drugs for treating pulmonary fibrosis is disclosed. PCSK9 inhibitor drugs can be further developed for the treatment of pulmonary fibrosis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an effect of PCSK9 in the treatment of pulmonary fibrosis, and an application of a PCSK9 inhibitor in the preparation of a medicine for treating pulmonary fibrosis.
Background
Pulmonary fibrosis (pulmonary fibrosis) is a diffuse pulmonary disease with unknown etiology and complex pathogenesis, and is currently recognized as the result of excessive repair after lung injury leading to excessive deposition of extracellular matrix. The pathogenesis of pulmonary fibrosis is unknown, and the repeated damage and over-repair of pulmonary alveolar epithelium are recognized as the key of the pathogenesis. The pathological characteristics are that chronic lung inflammation and alveolus persistent injury lead to extracellular Matrix Metalloproteinase (MMP) aggregation, especially MMP-2 and MMP-9 are abnormally increased, and metalloproteinase tissue inhibitor-1 (TIMP-1) is reduced, so that the balance relationship is destroyed, and a large amount of extracellular matrix aggregation, histiocyte reconstruction and collagen excessive deposition of the lung are caused. At the same time, it may inhibit the expression of Vascular Endothelial Growth Factor (VEGF) in the tissue, reduce the permeability of pulmonary venule, inhibit the division and proliferation of vascular endothelial cells and the regeneration of blood vessels, aggravate the damage of pulmonary tissue and finally lead to the diffuse interstitial pulmonary disease-pulmonary fibrosis. At present, no effective anti-fibrosis medicine exists, and the anti-fibrosis progress is reduced by using anti-inflammation glucocorticoid, but the curative effect is limited, and the adverse reaction is more. The current treatment method can not meet the clinical requirement, and more new medicines with good curative effect, less side effect and low price are required to be searched to control the disease progress, reduce the relapse and the complication and reduce the death rate.
Proprotein convertase subtilisin (PCSK 9) is a member of the proprotein convertase family, which is secreted in the liver as an inactive proenzyme. The size of the PCSK9 gene cDNA is 3617bp, and the PCSK9 protein consisting of 692 amino acids is encoded. The PCSK9 precursor undergoes intramolecular autocatalytic separation of its N-terminal propeptide within the endoplasmic reticulum, with the separated N-terminal propeptide attached to the catalytic region, allowing the mature PCSK9 protein to leave the endoplasmic reticulum and enter the secretory pathway. After PCSK9 is secreted extracellularly, the first epidermal growth factor-like region on the cell surface binds to low-density lipoprotein (LDL) receptors, and the PCSK9-LDL receptor complex can enter lysosomes for degradation, resulting in a decrease in the cell surface LDL receptor, i.e., PCSK9 levels are inversely correlated with LDL receptors. In addition, multiple studies show that the loss of the function of the mutation of the PCSK9 gene can obviously reduce the LDL-C level and the incidence rate of coronary heart disease of different human species. In view of the significant effect of inhibiting PCSK9 on reducing the incidence of LDL-C and coronary heart disease, multiple treatment regimens have been developing drugs that block PCSK9 for reducing the incidence of LDL-C and coronary heart disease.
PCSK9 inhibitors include two broad classes: 1. prevent PCSK9 binding to LDL-R, e.g., monoclonal antibodies, peptidomimetics (polypeptide inhibitors), mimobody protein drugs; 2. inhibit the expression of the PCSK9 molecule or interfere the secretion of the PCSK9 molecule, such as small molecule interfering RNA, antisense oligonucleotide, small molecule compound inhibitor and the like. The monoclonal antibody is a hot spot for new drug research due to high blocking efficiency, accurate target position and good stability. At present, PCSK9 targeted monoclonal antibody drugs on the market all around the world are drugs preventing PCSK9 from binding with LDL-R. Including evocolumab (ilouzumab) developed by the combination of ann (Amgen) and antralae (Astellas), under the trade name retatha (rebetan); alirocumab developed in combination with Semiflu (Sanofi) and Regener (Regeneron) under the trade name Praluent (Borida). Clinical researches find that the drug has good tolerance to hypercholesterolemia, and the incidence of adverse reactions of a placebo group and an active treatment group is not obviously different. The pfeiri company also designed a related vaccine drug, and patients received the vaccine once a year to achieve long-term LDL lowering. In addition, Inclisiran is a siRNA (small interfering RNA) drug, and unlike monoclonal antibodies which are directly combined with PCSK9 molecules, the Inclisiran can inhibit the expression of PCSK9 gene, so that LDL receptors are not degraded by PCSK9, and therefore, the intake of LDL particles by hepatocytes is improved, and the LDL level in blood is reduced. Inclisiran is prepared by binding lipid nanoparticles with GalNAc (N-acetylgalactosamine) using proprietary technology, and GalNAc can bind to sialoglycoprotein receptors ASGR1 and ASGR2 expressed on the surface of hepatocytes. This technique allows for subcutaneous administration and targeting to the liver.
Until now, relevant documents, patents and products for treating pulmonary fibrosis diseases by applying a PCSK9 inhibitor are not found. We find that the knock-out PCSK9 gene can obviously inhibit the formation of pulmonary fibrosis for the first time, and the PCSK9 inhibitor can obviously improve the pulmonary fibrosis.
Disclosure of Invention
The problems to be solved by the invention are as follows: the function of the PCSK9 gene in the mechanism of treating pulmonary fibrosis diseases is determined through animal models, and the application of the PCSK9 inhibitor in the preparation of products for treating pulmonary fibrosis diseases is also determined. According to the invention, by establishing a rat pulmonary fibrosis model, the PCSK9 gene plays a key role in pulmonary fibrosis pathogenesis, and the application value of the PCSK9 inhibitor in preparing a medicament for treating pulmonary fibrosis is discovered.
The technical scheme of the invention is as follows: the invention injects 5U/mL bleomycin solution into the neck trachea incision of a rat, 1 time per day, and 14 days continuously, and establishes a pulmonary fibrosis model. Through research, the PSCK9 gene knock-out can obviously increase MMP-2, MMP-9 and VEGF levels in pulmonary tissue of a pulmonary fibrosis mouse model, reduce TIMP-1 levels, and simultaneously can improve SOD and CAT enzyme levels in peripheral blood, thereby showing that the PSCK9 gene knock-out has an inhibiting effect on pulmonary fibrosis.
In the inhibitor capable of obviously blocking PCSK9, representative PCSK9 monoclonal antibody, PCSK9 polypeptide inhibitor, PCSK9 small-molecule compound inhibitor and PCSK9 small interfering RNA are respectively selected, and the rat model with pulmonary fibrosis is treated by tail vein injection and compared with a negative control group and a model group. The results show that the index of pulmonary fibrosis of the PCSK9 inhibitor group is obviously better than that of the model group, each PCSK9 inhibitor group has no systemic adverse reaction, rats are normal in activity and foraging, and no respiratory and central nervous system abnormal expression is seen. Experiments prove that the PCSK9 inhibitor can obviously improve pulmonary fibrosis laboratory indexes, and shows that the PCSK9 inhibitor has obvious therapeutic effect on pulmonary fibrosis.
It is well known to those skilled in the art that, based on the co-pathogenesis of the disease and the results shown in the above experiments, it is speculated that PCSK9 inhibitors (blockers) also have a therapeutic effect on its fibrotic disease. The PCSK9 inhibitors (blockers) may be used alone or in combination with other drugs or treatments, including traditional drugs and other targeted biologies.
Based on the above studies, the present invention relates to the use of a PCSK9 inhibitor (blocker) in the preparation of a medicament for the treatment of pulmonary fibrosis, wherein PCSK9 is proprotein convertase, bacillus subtilis convertase, belonging to the proprotein convertase family.
Preferably, the PCSK9 inhibitor (blocker) is a PCSK9 small molecule compound or PCSK9 interfering RNA or PCSK9 monoclonal antibody or PCSK9 mimetic peptide or PCSK9 mimetic antibody protein or PCSK9 antisense oligonucleotide or PCSK9 vaccine.
Further, the PCSK9 small molecule compound or PCSK9 interference RNA or PCSK9 monoclonal antibody or PCSK9 mimetic peptide or PCSK9 mimetic antibody protein or PCSK9 antisense oligonucleotide or PCSK9 vaccine is used for preparing the medicine for treating pulmonary fibrosis.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a new and better treatment method for the treatment of pulmonary fibrosis, and PCSK9 inhibitor (blocking agent) products for treating pulmonary fibrosis can be further prepared through the disclosure of the invention, so that new monomeric or compound preparations containing various PCSK9 inhibitors can be developed for treating pulmonary fibrosis. The existing research results prove that the medicine containing the PCSK9 inhibitor has the advantages of remarkable curative effect, small side effect and good tolerance, and can provide a series of new products with good curative effect, safety and economy for the market.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention; in the description and claims of the present application, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention, in addition to those described in the art and in accordance with the teachings of the present invention.
Example 1 effect of PSCK9 knock-out on rat pulmonary fibrosis model
1. Experimental methods
1.1 materials:
(1) reagent: bleomycin (4 mg/count, Tianjin Taihe pharmaceutical Co., Ltd.), mouse anti-mouse MMP monoclonal antibody (NEO Mark-ers Co., Ltd.), mouse anti-mouse TIMP-1 polyclonal antibody (Wuhan Boston Co., Ltd.), enzyme-linked immunosorbent assay (ELISA) Kit (R & D Co., USA), Quanstscript RT Kit reverse transcription Kit (TaKaRa Co., Ltd.).
(2) Experimental animals: SPF-level Wistar rats, PCSK 9-/-SPF-level Wistar rats (Pcsk 9 gene exon 2-3 is knocked out by using CRISPR gene editing technology to obtain Pcsk9 gene knocked-out rats), body weight (181 +/-22) g and males. The animal is derived from a Nanmo organism.
1.2 animal grouping and modeling
Rats were numbered according to body weight and divided into a blank control group, a model group, and a PCSK 9-/-group by a random permutation table method, with 6 rats each. Each group of rats was anesthetized by intraperitoneal injection with 2% sodium pentobarbital (120 mg/kg), fixed on an operating table, and subjected to cervical tracheotomy for drug injection. The blank control group was injected with physiological saline (1.25 mL/kg), and the model group and PCSK 9-/-group were injected with 5U/mL bleomycin solution (5 mg/kg) 1 time per day for 14 consecutive days.
1.3 Observation index and test method
The peripheral venous blood of each group of animals is taken through the tail vein at 14 days after the model building, and the levels of peripheral blood superoxide dismutase (SOD) and Catalase (CAT) are detected. After each group was bled, rats were sacrificed and right lung tissue from the animals was stored in a-4 ℃ freezer for detection of VEGF. Left lung tissue is embedded and sliced by conventional paraffin, and MMP subtype and TIMP-1 expression in rat lung tissue are detected by an immunohistochemical staining method. When detecting VEGF, taking out right lung tissue, grinding, homogenizing, centrifuging at 3000 r/min, collecting supernatant, detecting lung tissue VEGF protein by ELISA method, and determining VEGF-mRNA expression by reverse transcription polymerase chain method.
1.4 statistical methods
Data analysis was performed using SPSS 16.0 statistical software. The measured data are averaged + -SD: (xS), comparing by using one-factor variance analysis, and comparing two by using t test and P<A difference of 0.05 is statistically significant.
2. Results of the experiment
2.1 Effect of PSCK9 Gene knock-out on MMP in rat Lung tissues
The lung tissue TIMP-1 and MMP subtype of rats in the blank control group are slightly expressed. The MMP-2 and MMP-9 expressions of the rats in the model group are increased after model building, the TIMP-1 is reduced, and the difference has statistical significance (P is less than 0.05) compared with a blank control group, thereby indicating that the model building is successful. The expression of MMP-2 and MMP-9 in the PCSK 9-/-group is reduced, and the expression of TIMP-1 is up-regulated, and the difference is statistically significant compared with the model group (P < 0.05). See Table 1
TABLE 1 comparison of TIMP-1 and MMP expression in rat lung tissue groups (n =6, x. + -. s)
| Group of | TIMP-1 | MMP-2 | MMP-9 |
| Model control group | 5.71±0.63 | 3.86±0.29 | 5.17±0.39 |
| Blank spaceControl group | 8.95±0.56* | 2.41±0.18* | 3.29±0.22* |
| PCSK 9-/-group | 8.87±0.58* | 2.43±0.21* | 3.32±0.23* |
Note: p <0.05 compared to model control group.
2.2 Effect of PSCK9 Gene knock-out on VEGF in Lung tissues
The expression of VEGF protein and VEGF-mRNA in rat lung tissues of each group is shown in Table 2. The expression of VEGF protein and VEGF-mRNA in the model group is obviously reduced, and the difference has statistical significance (P is less than 0.05) compared with that of a blank control group, so that the success of modeling of the pulmonary fibrosis model is shown. The PCSK 9-/-group VEGF protein and VEGF-mRNA expression were statistically different compared to the model group (P < 0.05).
TABLE 2 comparison of VEGF protein and VEGF-mRNA expression levels in groups of lung tissues (n =6, x + -s)
| Group of | VEGF protein (pg/ml) | VEGF-mRNA |
| Model control group | 37.23±4.16 | 0.52±0.19 |
| Blank control group | 54.26±3.95* | 0.83±0.13* |
| PCSK 9-/-group | 56.12±3.67* | 0.85±0.15* |
Note: p <0.05 compared to model control.
2.3 Effect of knocking-out of PSCK9 Gene on SOD and CAT enzyme Activity in peripheral blood
The peripheral blood SOD and CAT enzyme levels of the rats in each group are shown in Table 3. The activity of SOD and CAT enzymes in peripheral blood of rats in the model group is reduced, and the difference has statistical significance (P is less than 0.05) compared with that of an empty control group; the peripheral blood SOD and CAT enzyme activities of rats in the PCSK 9-/-group are enhanced, and the differences compared with the model group have statistical significance (P < 0.05).
TABLE 3 comparison of SOD and CAT enzyme levels in peripheral blood of each group (n =6, x. + -. s)
| Group of | SOD（U/ml） | CAT（kU/g） |
| Model control group | 143.36±15.23 | 8.87±1.21 |
| Blank control group | 223.65±13.28* | 15.16±1.29* |
| PCSK 9-/-group | 221.76±13.57* | 14.98±1.32* |
Note: p <0.05 compared to model control.
3. Conclusion of the experiment
The PSCK9 gene knock-out can obviously reduce the levels of MMP-2 and MMP-9 in lung tissues of a pulmonary fibrosis mouse model, increase the levels of TIMP-1 and VEGF, and simultaneously can improve the levels of SOD and CAT enzymes in peripheral blood, thereby showing that the PSCK9 gene has an inhibiting effect on pulmonary fibrosis.
Example 2 effect of PSCK9 inhibitors on a rat model of pulmonary fibrosis
1. Experimental methods
1.1 materials:
(1) reagent: bleomycin (4 mg/count, Tianjin Taihe pharmaceutical Co., Ltd.), mouse anti-mouse MMP monoclonal antibody (NEO Mark-ers Co., Ltd.), mouse anti-mouse TIMP-1 polyclonal antibody (Wuhan Boston Co., Ltd.), enzyme-linked immunosorbent assay (ELISA) Kit (R & D Co., USA), Quanstscript RT Kit reverse transcription Kit (TaKaRa Co., Ltd.).
(2) SiRNA sequences and modifications
| Gene | 5'-3' Sense | 5'-3' Antisense |
| siPCSK9-1 | GccuGGAGuuuAuucGGAAdT*dT | UUCCgAAuAAACUCcAGGCdT*dT |
| siPCSK9-2 | AGGuGuAucuccuAGAcAcdT*dT | GUGUCuAGGAGAuAcACCUdT*dT |
(3) PCSK9 small molecule compound inhibitor (product R-IMPP of Selleck company), chemical formula: c24H27N3O2，Molecular weight: 389.49
(4) The PCSK9 monoclonal antibody was purchased from Abcam corporation (ab 81041)
(5) PCSK9 polypeptide purchased from Abcam company (ab 32727)
(6) Experimental animals: the Specific Pathogen Free (SPF) Wistar rat is half male and female, 51-55 days old, and 180 +/-21 g in body weight, and is from Nanjing medical university animal center.
1.2 animal grouping and modeling
Rats are numbered according to weight, and divided into a small molecule compound treatment group (PCSK 9 small molecule compound inhibitor for tail vein injection, 3mg/kg. d), a siPcsk9 treatment group (PCSK 9 small interfering RNA for tail vein injection, 3mg/kg. d), a monoclonal antibody treatment group (PCSK 9 monoclonal antibody for tail vein injection, 3mg/kg. d), a polypeptide treatment group (PCSK 9 polypeptide inhibitor for tail vein injection, 3mg/kg. d), a model group (physiological saline for tail vein injection, 3mg/kg. d), a blank control group (physiological saline for tail vein injection, 3mg/kg. d), 12 animals in each group, and male and female halves. Each group of rats was anesthetized by intraperitoneal injection with 2% sodium pentobarbital (120 mg/kg), fixed on an operating table, and subjected to cervical tracheotomy for drug injection. Normal saline (1.25 mL/kg) is injected into a control group, 5U/mL bleomycin solution (5 mg/kg) is injected into a model group and each treatment group, and corresponding PCSK9 inhibitor solution is injected into the tail vein of each treatment group, and the same amount of normal saline is injected into the tail vein of a blank control group and the tail vein of the model group 1 time a day for 14 days after the model is made.
1.3 Observation index and test method
The peripheral venous blood of each group of animals is taken through the tail vein after the model building and at the 14d treatment, and the levels of peripheral blood superoxide dismutase (SOD) and Catalase (CAT) are detected. The rats (6 per group, post-molding and treatment 14 d) were sacrificed in 2 aliquots after each group was bled and the right lung tissue of the animals was stored in a freezer at-4 ℃ for detection of VEGF. Left lung tissue is embedded and sliced by conventional paraffin, and MMP subtype and TIMP-1 expression in rat lung tissue are observed by an immunohistochemical staining method. When detecting VEGF, taking out right lung tissue, grinding, homogenizing, centrifuging at 3000 r/min, collecting supernatant, detecting lung tissue VEGF protein by ELISA method, and determining VEGF-mRNA expression by reverse transcription polymerase chain method.
1.4 statistical methods
Data analysis was performed using SPSS 16.0 statistical software. The measured data are averaged + -SD: (xS), comparing by using one-factor variance analysis, and comparing two by using t test and P<A difference of 0.05 is statistically significant.
2. Results of the experiment
2.1 Effect of PCSK9 inhibitors on MMP in rat Lung tissue
The lung tissue TIMP-1 and MMP subtype of rats in the blank control group are slightly expressed and have little change after modeling and 14d treatment. The MMP-2 and MMP-9 expressions of rats in the model group are increased after modeling and 14d treatment, and the TIMP-1 expression is reduced, and the difference is statistically significant compared with a blank control group (P is less than 0.05). As shown in Table 4, after 14d treatment, MMP-2 and MMP-9 expression were reduced and TIMP-1 expression was up-regulated in each PCSK9 inhibitor group, and the difference was statistically significant compared with the model group (P < 0.05).
TABLE 4 comparison of TIMP-1 and MMP expression in rat lung tissue of various groups (n =6, x. + -. s)
| Group of | TIMP-1 | MMP-2 | MMP-9 |
| Model set | 5.53±0.72 | 3.91±0.36 | 5.21±0.32 |
| Blank control group | 8.96±0.48* | 2.42±0.21* | 3.29±0.21* |
| Group of compounds | 8.56±0.58* | 2.67±0.32* | 3.43±0.34* |
| siPcsk9 treatment group | 8.24±0.45* | 2.98±0.26* | 3.56±0.25* |
| Monoclonal antibody treatment group | 7.87±0.51* | 3.24±0.28* | 3.64±0.27* |
| Polypeptide treatment group | 7.53±0.54* | 3.05±0.31* | 3.71±0.23* |
Note: p <0.05 compared to model control.
2.2 Effect of PCSK9 inhibitors on VEGF in Lung tissue
The VEGF protein and VEGF-mRNA expression in rat lung tissues of each group are shown in Table 5. After 14d of molding and treatment, the lung tissue VEGF protein and VEGF-mRNA expression of the rats in the blank control group have no obvious change (P is more than 0.05); the expression of VEGF protein and VEGF-mRNA in the model group is obviously reduced, and the difference has statistical significance compared with that of a blank control group (P < 0.05). After 14 days of treatment, the expression of VEGF protein and VEGF-mRNA of each PCSK9 inhibitor group is enhanced compared with that after model building, and the difference compared with the model group has statistical significance (P < 0.05).
TABLE 5 comparison of VEGF protein and VEGF-mRNA expression levels in groups of lung tissues (n =6, x + -s)
Note: p <0.05 compared to model control.
2.3 Effect of PCSK9 inhibitors on the Activity of SOD and CAT enzymes in peripheral blood
The peripheral blood SOD and CAT enzyme levels of the rats in each group are shown in Table 6. After 14 days of modeling and treatment, the activities of SOD and CAT enzymes in peripheral blood of rats in the blank control group have no obvious change (P is more than 0.05). The activity of SOD and CAT enzymes in peripheral blood of rats in the model group is reduced, and the difference has statistical significance (P is less than 0.05) compared with that of a blank control group; after 14 days of treatment, the peripheral blood SOD and CAT enzyme activities of rats in each PCSK9 inhibitor group are enhanced, and the differences compared with the model group have statistical significance (P < 0.05).
TABLE 6 comparison of SOD and CAT enzyme levels in peripheral blood of each group (n =6, x. + -. s)
Note: p <0.05 compared to model control.
3. Conclusion of the experiment
Each PCSK9 inhibitor can obviously reduce the levels of MMP-2 and MMP-9 in lung tissues of a pulmonary fibrosis mouse model, and increase the levels of TIMP-1 and VEGF; simultaneously, the SOD and CAT enzyme levels in peripheral blood can be improved, and the medicine has a therapeutic effect on pulmonary fibrosis.
Claims (3)
- Use of a PCSK9 inhibitor for the manufacture of a medicament for the treatment of pulmonary fibrosis, characterised in that PCSK9 is proprotein convertase, bacillus subtilis, family of proprotein convertases.
- 2. Use of a PCSK9 inhibitor for the manufacture of a medicament for the treatment of pulmonary fibrosis according to claim 1, wherein the PCSK9 inhibitor is a PCSK9 small molecule compound inhibitor or a PCSK9 interfering RNA or a PCSK9 monoclonal antibody or a PCSK9 mimetic peptide or a PCSK9 mimetic antibody protein or a PCSK9 antisense oligonucleotide or a PCSK9 vaccine.
- 3. The use of the PCSK9 inhibitor of claim 1 in the manufacture of a medicament for the treatment of pulmonary fibrosis, wherein the PCSK9 inhibitor is administered alone or in combination with other therapeutic methods or drugs to treat pulmonary fibrosis.
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| CN202011228305.XA CN114432447A (en) | 2020-11-06 | 2020-11-06 | Application of PCSK9 inhibitor in preparation of medicine for treating pulmonary fibrosis |
| US18/024,010 US20230346773A1 (en) | 2020-07-01 | 2021-06-30 | Use of pcsk9 inhibitor in preparation of product for treating multiple diseases |
| PCT/CN2021/103749 WO2022002160A1 (en) | 2020-07-01 | 2021-06-30 | Use of pcsk9 inhibitor in preparation of product for treating multiple diseases |
| EP21833682.4A EP4268817A1 (en) | 2020-07-01 | 2021-06-30 | Use of pcsk9 inhibitor in preparation of product for treating multiple diseases |
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