CN115869317A - Application of erlotinib in preparation of medicine for preventing/treating subretinal membrane generation after retinal detachment - Google Patents
Application of erlotinib in preparation of medicine for preventing/treating subretinal membrane generation after retinal detachment Download PDFInfo
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- CN115869317A CN115869317A CN202211629736.6A CN202211629736A CN115869317A CN 115869317 A CN115869317 A CN 115869317A CN 202211629736 A CN202211629736 A CN 202211629736A CN 115869317 A CN115869317 A CN 115869317A
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Abstract
The invention provides an application of erlotinib in preparing a medicine for preventing/treating subretinal membrane generation after retinal detachment. In animal experiments, 40mg/kg of erlotinib orally can effectively prevent the generation of the subretinal membrane after long-term retinal detachment, and can effectively remove the existing subretinal membrane for treatment. The integrity of the subretinal space tissue structures (retinal pigment epithelium, photoreceptor cell outer segments, etc.) was unaffected by treatment with this concentration of erlotinib. In cellular experiments, erlotinib at a concentration of 5uM was able to significantly inhibit fibronectin production by RPE cells and promote fibronectin degradation. Erlotinib can be demonstrated to prevent/or treat subretinal membrane production following retinal detachment.
Description
Technical Field
The invention belongs to the field of new medical application, and particularly relates to application of erlotinib in preparation of a medicine for preventing/treating subretinal membrane generation after retinal detachment.
Background
Subretinal membranes are one type of Proliferative Vitreoretinopathy (PVR). PVR is the main reason of failure of the restitution operation of the rhegmatogenous retinal detachment, and the pathological manifestations of the PVR are that extensive fibroproliferative membranes on the front surface and the back surface of the retina shrink and stretch to cause the retinal detachment. Currently, the clinical treatment of PVR is to remove the proliferation membrane by surgery, but since the subretinal membrane is located in the subretinal space, the removal requires making an incision through the retina, and the surgery operation is inevitable to cause irreversible damage to the subretinal space tissue structure. Therefore, the difficulty and complications of the subretinal surgery are greatly increased compared to the epiretinal membrane (ERM). How to remove the subretinal membrane while maintaining the in-situ state of the retina is a final goal of the improvement of the surgical mode. In addition, since much less is known about the pathogenesis of subretinal membranes, drug development targeting subretinal membranes is likewise challenging.
Disclosure of Invention
The invention aims to provide a new application of erlotinib in medicine preparation, and particularly provides an application of erlotinib in preparing a medicine for preventing/treating subretinal membrane generation after retinal detachment.
The invention provides a new medical application of the existing drug erlotinib. Erlotinib is a reversible tyrosine kinase inhibitor, can inhibit phosphorylation of a specific type of Epidermal Growth Factor Receptor (EGFR) -related intracellular tyrosine kinase, and is a first-line medicament for patients with locally advanced or metastatic non-small cell lung cancer with sensitive mutation of the EGFR gene. However, no treatment for PVR has been reported.
The research shows that the sequencing of single cell transcriptome of human subretinal surgery specimens shows that the main cells and extracellular matrix components of the subretinal membrane are derived from RPE cells, the cell self-weighing and extracellular matrix components of subretinal proliferation in an animal retinal detachment model are highly similar to those of human, and the EGFR phosphorylated at the Tyr1068 site is specifically expressed in the subretinal membrane after surgical excision and animal modeling. In animal experiments, 40mg/kg of erlotinib orally can effectively prevent the generation of the subretinal membrane after long-term retinal detachment, and can effectively remove the existing subretinal membrane to play a role in treatment. The integrity of the subretinal space tissue structures (retinal pigment epithelium, photoreceptor cell outer segments, etc.) was unaffected by treatment with this concentration of erlotinib. In cellular experiments, erlotinib at a concentration of 5uM was able to significantly inhibit fibronectin production by RPE cells and promote fibronectin degradation. It was demonstrated that erlotinib can prevent/or treat subretinal membrane production following retinal detachment.
Drawings
FIG. 1 is a graph of the single cell transcriptome sequencing of human subretinal surgery specimens of the different cell types in the examples.
FIG. 2 is a diagram of single cell transcriptome sequencing analysis of human subretinal surgery specimens of the examples.
FIG. 3 is an immunofluorescence plot of retinal pigment epithelial cells treated with different concentrations of erlotinib in the examples.
FIG. 4 is an immunofluorescence plot of retinal pigment epithelial cells treated with different concentrations of erlotinib in the examples.
FIG. 5 is a real-time quantitative PCR graph of retinal pigment epithelial cells treated with different concentrations of erlotinib in the examples.
FIG. 6 is an immunofluorescent staining chart of an eyeball section of a mouse with retinal detachment in the example.
FIG. 7 is an immunofluorescent staining chart of an eyeball section of a mouse with retinal detachment in the example.
FIG. 8 is an immunofluorescent staining chart of an eyeball section of a mouse with retinal detachment in the examples.
Detailed Description
In order to make the technical solutions better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only partial embodiments of the present application, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the terms "comprises" and "comprising," and any variations thereof, in the description and claims of this application and the above-described drawings, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
PCA clustering is carried out on the sequencing data of the single-cell transcriptome of the human subretinal surgery specimen, different cell clusters are defined by taking specific markers expressed by the cells as the basis, and the proportion of each cell type is calculated. The results obtained are shown in FIG. 1, confirming that the cell type of the subretinal membrane is mainly RPE-derived.
The method comprises the steps of respectively carrying out channel enrichment on cells in a normal RPE differentiation intermediate state and cells in a pathological dedifferentiation intermediate state to find a consistent gene set (figure 2 left) which is crucial in the differentiation/dedifferentiation process, extracting genes in the consistent channels, and screening out a specific expression gene Top 1-EGFR (figure 2 right) in the dedifferentiation process according to descending order of the expression ratio of the genes in a disease group. In vitro experiments:
RPE cells were treated with erlotinib (MCE, HY-50896), an EGFR inhibitor, at various concentrations (0um, 2um, 5um), for 72 hours, and a significant decrease in FN1 expression was observed with increasing concentration by immunofluorescence staining fibronectin (fibronectin, FN 1) (indicated by white triangular arrows in the figure) (as shown in fig. 3).
RPE cells were plated on fibronectin pre-treated crawlers and treated with erlotinib (MCE, HY-50896), an EGFR inhibitor, at various concentrations (0um, 2um, 5um), for 48 hours, and a decrease in extracellular fibronectin component was observed as the concentration of erlotinib increased (as shown in fig. 4).
RPE cells were treated with erlotinib (MCE, HY-50896), an EGFR inhibitor, at various concentrations (0um, 2um, 5um), for 72 hours, and real-time quantitative PCR demonstrated that erlotinib was able to significantly inhibit RPE FN1 expression, up-regulate BEST1 expression (as shown in fig. 5), thereby demonstrating the ability to inhibit RPE fibrosis.
In vivo experiments:
the C57BL/6J mice were subjected to long-term retinal detachment by injecting a sodium hyaluronate gel (LOT: 22206281)/PBS mixture (50%, v/v) through the subretinal space, and it was confirmed that the RPE layer was discontinuous (indicated by white triangular arrow in the upper left of FIG. 6) and fibrosis occurred (elevated FN1 expression, indicated by white triangular arrow in the upper right of FIG. 6). An additional small number of microglia accumulate in the subretinal space (lower left white arrow in fig. 6) and keratin expression is increased (lower right white arrow in fig. 6). The constructed animal model of the subretinal membrane was confirmed to be consistent with the subretinal membrane cell types shown by the human single cell data.
The C57BL/6J mice were subjected to long-term retinal detachment by injecting a sodium hyaluronate gel (LOT: 22206281)/PBS mixture (50%, v/v) into the subretinal space, and it was confirmed that the RPE cells were fibrotic due to the long-term retinal detachment (elevated FN1 expression, indicated by white triangular arrows). Mice were gavaged with 40mg/kg of erlotinib (MCE, HY-50896) or vehicle in dissolved Drug (DMSO) starting on day 2 after molding for 7 consecutive days, and the eyeballs were removed on day 10 to compare the expression of sub-retinal RPE cells FN1 (as shown in fig. 7). Erlotinib was found to significantly inhibit RPE fibrosis due to retinal detachment (fig. 7 below). The preventive effect of erlotinib on subretinal membranes was demonstrated.
The C57BL/6J mice were subjected to long-term retinal detachment by injecting a sodium hyaluronate gel (Shanghai Jianhua Fine biologicals Co., ltd., LOT: 22206281)/PBS mixture (50%, v/v) through the subretinal space, and it was confirmed that the RPE cells were fibrotic (FN 1 expression is elevated, as indicated by the white triangular arrow at the upper right in FIG. 8) and the retinal pigment epithelial cells were migratory and proliferated (RPE 65 is thickened to form multilayers, as indicated by the white triangular arrow at the upper left in FIG. 8). Mice were gavaged with 40mg/kg of erlotinib (MCE, HY-50896) or vehicle in dissolved Drug (DMSO) starting on day 5 after molding for 7 consecutive days, and the eyeballs were removed on day 12 to compare the expression of subretinal RPE cells FN1 and RPE 65. Erlotinib was found to significantly inhibit RPE fibrosis due to retinal detachment (lower right in fig. 8) and maintain the state of the RPE65 monolayer (lower left in fig. 8). The therapeutic effect of erlotinib on subretinal membranes was demonstrated.
It could therefore be demonstrated that erlotinib can prevent/or treat subretinal membrane production following retinal detachment.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.
Claims (1)
1. Use of erlotinib for the manufacture of a medicament for the prevention/treatment of subretinal membrane production following retinal detachment.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211629736.6A CN115869317A (en) | 2022-12-19 | 2022-12-19 | Application of erlotinib in preparation of medicine for preventing/treating subretinal membrane generation after retinal detachment |
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| CN202211629736.6A CN115869317A (en) | 2022-12-19 | 2022-12-19 | Application of erlotinib in preparation of medicine for preventing/treating subretinal membrane generation after retinal detachment |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015029948A1 (en) * | 2013-08-26 | 2015-03-05 | リンク・ジェノミクス株式会社 | Prophylactic or therapeutic agent for retinal disease caused by retinal pigment epithelium disorder |
| US20190275044A1 (en) * | 2016-05-19 | 2019-09-12 | Konkuk University Industrial Cooperation Corp | Pharmaceutical composition containing keratin 8 phosphorylation inhibitor for preventing or treating macular degeneration, and method for screening macular degeneration medicine |
| WO2021180867A1 (en) * | 2020-03-11 | 2021-09-16 | Universität Regensburg | A nanoparticle for use in the treatment of an ocular disease |
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- 2022-12-19 CN CN202211629736.6A patent/CN115869317A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015029948A1 (en) * | 2013-08-26 | 2015-03-05 | リンク・ジェノミクス株式会社 | Prophylactic or therapeutic agent for retinal disease caused by retinal pigment epithelium disorder |
| US20190275044A1 (en) * | 2016-05-19 | 2019-09-12 | Konkuk University Industrial Cooperation Corp | Pharmaceutical composition containing keratin 8 phosphorylation inhibitor for preventing or treating macular degeneration, and method for screening macular degeneration medicine |
| WO2021180867A1 (en) * | 2020-03-11 | 2021-09-16 | Universität Regensburg | A nanoparticle for use in the treatment of an ocular disease |
Non-Patent Citations (2)
| Title |
|---|
| WEI ZHANG等: "EGF Receptor Signaling Modulates YAP Activation and Promotes Experimental Proliferative Vitreoretinopathy", IOVS, vol. 63, no. 8, pages 1 - 10 * |
| 宋惠欣等: "表皮生长因子在眼科疾病中的作用", 眼科新进展, vol. 37, no. 05, pages 484 - 487 * |
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