Methods and medicaments for treating endometriosis

Abstract

Methods and medicaments are provided for treating endometriosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a sphingosine-1-phosphate receptor 1 (S1PR1)-antagonist.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to PCT International Application No. PCT / CN2023 / 112244, filed on August 10, 2023, which is incorporated herein by reference in its entirety.

[0003] field

[0004] This invention relates to the medical field, and in particular to a method for treating endometriosis.

[0005] background

[0006] Endometriosis is a chronic inflammatory gynecological disease characterized by the presence of ectopic endometrial glands and stroma, primarily located in the pelvic peritoneum, ovaries, and rectovaginal septum. It is estimated that approximately 5-15% of women of reproductive age worldwide have endometriosis (PMID: 27159755), while the prevalence can reach 35-80% in women experiencing pelvic pain and / or infertility (PMID: 32212520, 33640070). Due to the variable symptoms and the ease with which endometriosis symptoms can be confused with those of other diseases, diagnosis is often delayed, with an average delay of 4 to 12 years (PMID: 8671344, 22990516, 12790847, 28440744). The etiology of endometriosis is unclear, and several hypotheses have been proposed to explain the origin of this disease (PMID: 30026507 review). From a pathological perspective, genetic factors, environmental factors, immune dysfunction, and estrogen imbalances can all contribute to the formation and maintenance of endometriosis lesions (PMID:30026507). Among these, steroid production disorder is the most studied mechanism in the pathology of endometriosis, which can manifest as abnormal changes in hormone levels, and abnormal hormone levels are a common risk factor for this disease.

[0007] Due to the complexity and diversity of its pathogenesis, endometriosis remains incurable. Various treatment methods have been employed to address both endometriosis and infertility, including surgery, medication, and acupuncture. Hormone therapy is considered the first-line treatment for endometriosis. In multiple Phase III clinical trials, two approved hormonal drugs, Elagolix and Myfembree, demonstrated their effectiveness in relieving pain caused by endometriosis without any safety issues (PMID: 28525302, 29889764, 34134684, 33066973, 35717987).

[0008] Although endometriosis is not fatal, chronic pain and infertility can significantly impact quality of life. It is estimated that the economic burden of endometriosis in the United States alone reaches $80 billion annually (PMID: 35620300). Nevertheless, mounting evidence suggests that endometriosis is a systemic disease that alters cardiovascular, neurological, metabolic, and immune function (PMID: 33640070). Patients may have an increased risk of developing a variety of chronic diseases, such as adenomyosis (PMID: 24532217), ovarian cancer (PMID: 28240000), and autoimmune diseases (PMID: 31260048). These factors collectively underscore the need for innovative and effective treatments for this disease. To address this, we utilized the AI-driven target discovery platform PandaOmics to identify S1PR1 as a repurposed candidate for treating endometriosis.

[0009] Overview

[0010] The purpose of this invention is to provide a treatment or medicine for endometriosis.

[0011] One aspect of the present invention provides a method for treating endometriosis in an individual in need, comprising administering to the individual an effective amount of a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist.

[0012] In some embodiments, the S1PR1 antagonist is selected from one or more of the following: Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, Ceralifimod, PF-04629991, and their derivatives.

[0013] Another aspect of the invention provides the use of a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist in the preparation of a medicament for the treatment of endometriosis.

[0014] In some embodiments, the S1PR1 antagonist is selected from one or more of the following: bonesimod, ozanimod, cibonimod, fingolimod, eltrimod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cirafimod, PF-04629991, and their derivatives.

[0015] Another aspect of the invention provides a medicament for treating endometriosis, wherein the medicament comprises a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist.

[0016] In some embodiments, the S1PR1 antagonist is selected from one or more of the following: bonesimod, ozanimod, cibonimod, fingolimod, eltrimod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cirafimod, PF-04629991, and their derivatives. Brief description of the attached diagram

[0018] Figure 1A-1D Computer analysis showing the association between S1PR1 and endometriosis. Figure 1A This is a screenshot of the target identification page from PandaOmics' meta-analysis on endometriosis. S1PR1 was identified as a potential druggable target for endometriosis. This analysis used gene expression, genetics, drug, and textual data. Figure 1B Thirty-one endometrial samples from GSE179640 were divided into five groups: ovarian endometriosis, peritoneal endometriosis and adjacent tissues, in situ endometrium, and a control group. Cells identified by scRNA-seq data were pooled and then clustered into 18 clusters. Figure 1C The expression intensity of S1PR1 in each cell cluster is shown in the t-SNE plot. Figure 1D This section illustrates the dysregulation of S1PR1-related pathways in comparisons of endometriosis. These pathways were annotated using the Reactome database, and the degree of pathway dysregulation was determined using the iPANDA algorithm. Green and red bars represent the number of comparisons of significant activation and inactivation of the corresponding pathways, respectively.

[0019] Figure 2A-2BShow the expression of S1PR1 in GSE203191. Figure 2A Based on disease diagnosis and symptom observation, 33 menstrual discharge samples were divided into three groups: a diagnostic group, a symptom group, and a control group. Cells identified by scRNA-seq data from each group were merged and then clustered into 19 clusters. Figure 2B The expression intensity of S1PR1 in the cell cluster is shown in the t-SNE plot. invention Detailed Explanation

[0021] It should be understood that the present invention is not limited to the specific embodiments described herein. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting, as the scope of the invention is defined only by the appended claims.

[0022] Unless otherwise defined, 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 pertains. While any methods and materials similar to or equivalent to those described herein may be used to practice or test the invention, preferred methods and materials will be described below. All publications mentioned herein are for the purpose of disclosure and description of methods and / or materials in connection with reference to those publications.

[0023] If a given range of values ​​contains one or two boundaries, it should be understood that the smaller range between any intermediate value within the given range and either boundary of the range is also included in this invention. If a given range contains one or two boundaries, the range excluding one or both boundaries is also included in this invention.

[0024] the term

[0025] It must be noted that, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” used herein and in the appended claims include plural references. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended to provide a basis for the use of exclusive terms such as “only,” “unique,” ​​or negative qualifiers in the description of claim elements.

[0026] Unless otherwise stated, the terms “comprising,” “including,” “containing,” and variations thereof do not imply the exclusion of other members, components, integers, or steps. These terms also include the meaning of “consisting of.” The term “consisting of” is a specific embodiment of the term “comprising,” in which any other unstated member, component, integer, or step is excluded.

[0027] The term "about" refers to a range equal to plus or minus 10 percent (+ / - 10%) of a specific value.

[0028] The term “and / or” refers to any one, several or all of the elements connected by the term.

[0029] The term “endometriosis” as used in this article refers to the abnormal presence of tissue containing typical endometrial granules and stromal components in the pelvic cavity or other parts of the body (most commonly the abdominal cavity).

[0030] As used herein, the term "treatment" refers to the relief, suppression, and / or reversal of disease progression (e.g., endometriosis). The term "treatment" includes any marker of successful treatment or improvement of the disease, including any objective or subjective parameters such as reduction; remission; symptom relief or increased tolerance of the injury, pathological condition, or symptom to an individual; delay or slowing of the rate of progression, etc. The determination of treatment or improvement may be based on the results of physical examinations, pathological tests, and / or diagnostic tests known in the art, for example. Treatment may also refer to a reduction in the incidence or flare rate of the disease, or its recurrence rate (e.g., prolonged remission time), compared to inaction. Clinically, such treatment may also be referred to as prevention.

[0031] As used in this article, the term "active agent" refers to a pharmaceutically active chemical substance that provides some pharmacological action and is used to treat or prevent diseases such as endometriosis.

[0032] The terms “inhibitor” and “antagonist” as used herein are used interchangeably and refer to any molecule that partially or completely blocks or inhibits the activity of a target (e.g., a protein used as a target in this invention).

[0033] As used herein, the term "derivative" of a compound means any pharmaceutically acceptable molecule derived from (i.e., structurally related to) the compound and having similar or substantially the same activity as the compound, which, when administered to an individual, can (directly or indirectly) provide an active agent or its active metabolite. Examples of derivatives include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or metabolites.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid salt of the compounds of this invention. These salts can be prepared in situ during the final separation and purification of the compounds, or by reacting the purified compound in its free form alone with a suitable organic or inorganic acid and separating the resulting salt. Representative acid salts include, but are not limited to, acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, cyclamates, ethanedisulfonates, ethanesulfonates, formates, fumarates, gluceptates, gluconates, glucuronates, hexafluorophosphates, and hydroxybenzoylbenzene salts. (benzate), hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethyl sulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, glycosidate, stearate, succinate, tannic acid salt, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate salt. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride / chloride salt.

[0035] As used herein, the term "solvent" refers to a complex of variable stoichiometry formed by a solute (e.g., the active agent of the present invention) and a solvent. Such a solvent used for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid.

[0036] As used herein, the term "prodrug" refers to a precursor that, when applied to a biological system, produces the compound as a product. For example, a prodrug may have the structure X-drug, where X is an inert carrier moiety and the drug is the active compound.

[0037] As used herein, the term "metabolite" refers to a molecule produced by modifying or processing a compound after administration to an individual. The term "metabolite" can also refer to a modified or processed drug that retains at least some of the activity of the parent compound.

[0038] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with individual tissues without excessive toxicity, irritation, allergic reactions, or other problematic complications commensurate with a reasonable benefit / risk ratio.

[0039] As used in this article, the term "pharmacologically acceptable carrier" refers to any carrier that, when administered to an individual, has substantially no long-term or permanent harmful effects, such as stabilizers, diluents, additives, adjuvants, excipients, etc. A "pharmacologically acceptable carrier" should be a pharmaceutically inert material that is substantially non-biologically active and constitutes an important part of the formulation.

[0040] As used herein, the term "individual" means any organism to which the active agent of the compositions of the present invention may be administered, for example for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical individuals include animals (e.g., mammals such as mice, rats, rabbits, non-human primates such as chimpanzees and other ape and monkey species, and humans). Individuals can be mammals, particularly humans, including males or females, and include newborns, infants, juveniles, adolescents, adults, or the elderly, as well as different races and ethnicities.

[0041] As used herein, the terms "therapeutic effective dose" or "effective dose" are used interchangeably with "therapeutic effective amount" or "effective amount," referring to an amount effective in treating a disease (e.g., endometriosis) as recorded through clinical testing and evaluation, patient observations, etc. "Effective amount" may further specify the amount that results in a detectable change in biological or chemical activity. Those skilled in the art can detect and / or further quantify the detectable change in relation to the relevant mechanism or process. Furthermore, "effective amount" may specify the amount that maintains a desired physiological state, i.e., reduces or prevents a significant decline in the condition and / or promotes improvement in the condition.

[0042] As used herein, the term "unit dosage form" refers to a physically dispersed unit (e.g., capsule, tablet, or loaded syringe) suitable as an individual unit dose, each unit containing a predetermined amount of active agent calculated in conjunction with the desired pharmaceutical carrier to produce the desired therapeutic effect.

[0043] As used herein, the term "unit dose" refers to the dose of a substance (e.g., the active agent of the present invention) in a unit dosage form.

[0044] Active agent used to treat endometriosis

[0045] Through extensive research, the inventors have discovered a target for the treatment of endometriosis: sphingosine-1-phosphate receptor 1 (S1PR1). Antagonists or agonists of this target can be used to treat endometriosis.

[0046] Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1PR1), also known as endothelial differentiation gene 1 (EDG1), is a protein encoded by the S1PR1 gene in humans. S1PR1 is a G protein-coupled receptor that binds to the biologically active signaling molecule sphingosine-1-phosphate (S1P). S1PR1 belongs to a five-member (S1PR1-5) subfamily of sphingosine-1-phosphate receptors. S1PR1 was initially identified as an abundant transcript in endothelial cells and plays a crucial role in regulating endothelial cytoskeleton structure, migration, capillary-like network formation, and angiogenesis. Furthermore, S1PR1 signaling is essential in the regulation of lymphocyte maturation, migration, and transport.

[0047] The active agent used to treat endometriosis can be any one of the S1PR1 antagonists, including but not limited to bonesimod, ozanimod, cibonimod, fingolimod, eltromod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cirafimod, PF-04629991 and their derivatives.

[0048] The structure of an exemplary S1PR1 antagonist is shown below.

[0049]

[0050]

[0051]

[0052] The amount of each active agent in a unit dosage form can be 1-1000 mg, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg or any range between any two of the above specific values.

[0053] application

[0054] Each active agent of the present invention can be administered to an individual via oral, sublingual, rectal, vaginal, parenteral, intradermal, or nasal routes. Parenteral administration includes intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, intratumoral, transdermal, transarticular, intramural, intrasynovial, intrathecal, intrahepatic, intralesional, or intracranial injection or infusion.

[0055] The active agents used herein can be formulated into pharmaceutical compositions for administration using known techniques. See, for example, Remington, The Science and Practice of Pharmacy (9th edition, 1995). In the preparation of pharmaceutical compositions according to the invention, the active agent is typically mixed, particularly with a pharmaceutically acceptable carrier. Of course, the carrier must be acceptable in the sense of compatibility with any other component in the formulation and must not be harmful to the patient. The carrier can be solid or liquid, or both, and is preferably formulated with the compound into a unit-dose formulation, such as a tablet, which may contain 0.01% or 0.5% to 95% or 99% of the active agent by weight. One or more active agents can be incorporated into the formulations of the invention, which can be prepared by any well-known pharmaceutical technique, including mixing components, optionally including one or more excipients and / or excipients. In some embodiments, any composition, carrier, excipient, excipient, and / or formulation of the invention comprises an ingredient from a natural or non-natural source. In other embodiments, any component of the composition, carrier, excipient, excipient, and / or formulation of the invention may be provided in a sterile form. Non-limiting examples of sterile carriers include endotoxin-free water or pyrogen-free water.

[0056] In some embodiments, the pharmaceutical compositions of the present invention are provided as part of a sterile composition / preparation, comprising the active agent of the present invention and a pharmaceutically acceptable carrier and / or excipient.

[0057] Suitable dosage forms for oral administration include tablets, capsules, powders, pills, granules, suspensions, solutions or solution preconcentrates, emulsions or emulsion preconcentrates. Pharmaceutically acceptable carriers that can be used in oral dosage forms include water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Carriers such as starch, sugars, microcrystalline cellulose, diluents, fillers, flow aids, granulating agents, lubricants, binders, stabilizers, and disintegrants can be used to prepare oral solid dosage forms, such as powders, capsules, or tablets.

[0058] Diluents include, but are not limited to, microcrystalline cellulose, mannitol, powdered sugar, compressible sugar, dextran, dextrin, spinose, lactose, cellulose powder, sorbitol, sucrose, and talc, or combinations thereof. Based on the total weight of the oral composition, the diluent can be 5% to 90%, preferably 10% to 80%, 20% to 70%, 30% to 60%, or 40% to 50%.

[0059] Disintegrants include, but are not limited to, cellulose, alginate, gum, cross-linked polymers such as crospovidone or crospovidone, crospovidone sodium carboxymethyl cellulose, crospovidone calcium carboxymethyl cellulose, soybean polysaccharide, sodium starch glycolate, guar gum, or any combination thereof. The disintegrant may be present in an amount of about 1% to 15%, preferably 2% to 10%, based on the total weight of the oral composition.

[0060] The binder includes, but is not limited to, starch, cellulose or derivatives thereof, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, glucose, corn syrup, polysaccharides, gelatin or any combination thereof. Based on the total weight of the composition, the binder may be present in an amount of about 0.01 to 10%, preferably 1% to 10%.

[0061] Gliding agents include, but are not limited to, colloidal silica, magnesium trisilicate, cellulose powder, talc, or combinations thereof. Based on the total weight of the composition, the gliding agent may be present in an amount of 0.1% to 10%, preferably 0.1% to 0.5%.

[0062] Dosage forms may be, for example, tablets or capsules, and the effective dose may be provided in the form of one or more tablets, capsules, etc., and may be provided once daily or throughout the day at intervals of, for example, 4, 8, or 12 hours. For example, tablets or capsules may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, or 1,250 mg of active agent. For example, administration of the active agent of the present invention to a human individual may include a daily dose in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg, which may be administered entirely once daily or in portions throughout the day. Liquid formulations may also be prepared so that any dose can be easily and conveniently dispensed.

[0063] Parenteral dosage forms are preferably sterile or capable of being sterilized before administration to an individual. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dried products that can be dissolved or suspended in pharmaceutically acceptable injectable carriers, injectable suspensions, and emulsions.

[0064] Suitable carriers that can be used to provide the parenteral dosage forms provided herein include, but are not limited to: water for injection; aqueous media, such as, but not limited to, sodium chloride injection, Ringer's solution, and glucose injection; water-miscible carriers, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0065] Compounds that increase the solubility of one or more of the active agents disclosed herein may also be incorporated into the parenteral dosage forms provided herein. For example, cyclodextrins and their derivatives can be used to improve the solubility of the active agents of the present invention.

[0066] It should be understood that the effective therapeutic dose can be determined by the physician based on factors such as the type, stage and / or severity of the disease, the individual's condition, age, weight, sex and response, and the route of administration.

[0067] The therapeutically effective dose is such that, when administered to an individual, it is sufficient to achieve plasma concentrations of about 0.01 μg / ml to about 100 μg / ml, about 0.1 μg / ml to about 10 μg / ml, and about 1 μg / ml to 5 μg / ml.

[0068] When the active agents of the present invention are administered to an individual, the therapeutically effective amount of each active agent of the present invention is typically from about 0.5 to about 250 mg / kg, from about 1 to about 250 mg / kg, from about 2 to about 200 mg / kg, from about 3 to about 120 mg / kg, from about 5 to about 250 mg / kg, from about 10 to about 200 mg / kg, or from about 20 to about 120 mg / kg. In some implementations, the effective therapeutic dose may be 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 20 mg / kg, 25 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 75 mg / kg, 100 mg / kg, 120 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, or 300 mg / kg.

[0069] Each active agent of the present invention may be applied once or twice daily; or once every 2, 3, 4, 5, 6, 7, 8, 9, or 10 days; or once every 1, 2, or 3 weeks. In some embodiments, each active agent of the present invention may be applied in a five-times-a-week regimen. In a five-times-a-week regimen, it may be applied for five consecutive days (once a day), followed by two consecutive days of rest.

[0070] As used herein, the term "kit" refers to packaging and, generally, instructions for use. The active agent or pharmaceutical composition in a kit may be in any of a variety of forms suitable for distribution in the kit. Such forms may include liquids, powders, tablets, suspensions, etc. Two or more active agents may be provided in separate containers suitable for individual administration, or in a composition in a single container within the packaging. Depending on the treatment method, the kit may contain an amount sufficient for a dose of one or more active agents. Instructions for use typically contain written instructions on how to treat a disease (e.g., ALS) with the active agent in the kit.

[0071] It should be understood that, in addition to the active agent of the present invention, the combination or pharmaceutical composition of the present invention may include other therapeutic agents or therapies, such as biological therapeutic agents and / or chemotherapeutic agents. In addition to applying the active agent of the present invention, the method may include applying other therapeutic agents or therapies, such as biological therapeutic agents and / or chemotherapeutic agents. Other therapeutic agents or therapies may be applied simultaneously, alone, or sequentially with the therapeutic agents of the present invention.

[0072] Example

[0073] Example 1. Using PandaOmics TM -AI-enabled biological target discovery platform for identifying intrauterine targets Therapeutic targets and drug reuse candidates for membranes

[0074] 1. Method

[0075] Data sources and availability

[0076] The current analysis utilized batch and single-cell transcriptomics and proteomics data. A total of 36 endometriosis-related batch transcriptomics datasets from various tissue sources, retrieved from GeneExpression Omnibus (GEO) and ArrayExpress, including microarrays and RNA sequencing series, were available for direct downstream analysis and target identification using PandaOmics. Two single-cell transcriptomics datasets, GSE179640 and GSE203191, were also extracted from GEO.

[0077] Datasets and Comparison Selection

[0078] Since the pathogenesis of the disease begins with the situ endometrium, endometrial tissue datasets were selected for downstream analysis and target identification. Eleven case-control comparisons were generated from the eleven batch transcriptomics datasets listed in Table 1. Normal endometrial tissue from healthy individuals and situ endometrial tissue from patients with endometriosis were selected as controls, labeled "healthy" and "situ endometrium" respectively in the experimental design column of Table 1.

[0079] Table 1. Meta-analysis comparison of endometriosis for target selection

[0080]

[0081] PandaOmics target identification

[0082] PandaOmics is a cloud-based target discovery platform that combines multiple deep learning models and AI algorithms in the target prioritization process. Twenty-three target prioritization models have been developed, covering omics (Omics), text-based, financial, and key opinion leader (KOL) data, to predict the association between target genes and specific indications. Each model is scored on a normalized scale from zero to one, with higher scores corresponding to better predicted target-disease associations. These models are validated using time-machine methods to demonstrate their capabilities in target identification. The target list can also be refined using adjustable filters based on drugability, tissue specificity, target family, and development status.

[0083] To identify potential targets for endometriosis, a case-control batch transcriptomics comparison was assigned to a meta-analysis. To identify actionable targets with varying levels of novelty, filter and scoring settings were customized to re-prioritize targets. Only targets belonging to druggable protein classes were retained in the analysis, excluding those considered essential genes as defined by the Therapeutic Target Database (TTD). Therefore, three lists of druggable targets were generated: high confidence, moderate novelty, and high novelty, with the top 50 targets undergoing further analysis.

[0084] Single-cell transcriptomics data processing and analysis

[0085] For GSE203191, menstrual flow samples were collected from 11 individuals with diagnosed endometriosis, 13 symptomatic individuals (undiagnosed but with symptoms of chronic endometriosis), and 9 control individuals. Samples in GSE179640 were collected from five regions: healthy endometrium, situ endometrium from patients with endometriosis, ectopic endometriotic tissue from the ovaries and peritoneum, and tissue near endometriotic lesions in the peritoneum.

[0086] For GSE203191, the sample data matrix generated by Cell Ranger was retrieved from the GEO database, and gene and cell filtering and cell cluster annotation were performed according to the definitions in the original literature (PMID: 36104692). For GSE179640, the authors readily provided processed data including calibrated expressions, cell cluster annotations, sample metadata, and dimensionality-reduced coordinates, and extracted them from [the original literature]. https: / / singlecell.jax.org / datasets / endometriosis-2022Search. Differential gene expression between different cell clusters or sample groups was calculated using log-normalized count data and the Wilcoxon rank sum test.

[0087] Pathway analysis

[0088] Signaling pathway activation status was assessed using Ipanda (PMID: 27848968), a proprietary single-network model from PandaOmics. By combining differential gene expression data with pathway topological decomposition, iPANDA robustly identified multiple sets of biologically relevant pathway features from the input data and significantly reduced noise. iPANDA values ​​of 1 and -1 represent pathway activation and inhibition, respectively. The hierarchical structure of signaling pathways was curated based on the Reactome database.

[0089] 2. Results

[0090] Identifying S1PR1 as a potential therapeutic target using PandaOmics

[0091] Based on expression correlation results, target identification was performed using a meta-analysis of endometriosis with non-specific comparisons of 11 subtypes and cycles (Table 1). To identify potential therapeutic targets for endometriosis, high-confidence targets associated with the disease were screened based on rankings calculated by PandaOmics, consistency of dysregulated expression in comparisons included in the meta-analysis, statistical significance of the dysregulation, and literature support indicating potential roles in driving or promoting endometriosis. S1PR1 was ranked 223rd in the meta-analysis and scored at least 0.8 in four omics AI scoring models (i.e., network neighbor, expression, heterogeneous graph walk, and matrix factorization). Figure 1A ).

[0092] Upregulation of S1PR1 was observed in endometriosis transcriptomic datasets.

[0093] To investigate the functional association between S1PR1 and endometriosis, the expression profiles of S1PR1 were analyzed between samples collected from endometriotic lesions and control endometrium. Regarding batch transcriptomic characteristics, S1PR1 was upregulated in 10 out of 11 comparisons (90.9%), with 6 of these upregulations reaching statistical significance (FDR < 0.05) (Table 2). Two single-cell transcriptomic datasets for endometriosis, GSE179640 and GSE203191, were also extracted to investigate cell-specific expression profiles.

[0094] Table 2. Expression profiles of S1PR1 in batch transcriptomic comparisons in endometriosis

[0095]

[0096] GSE179640 consisted of control samples collected from endometrium, virgin endometrium from patients, ectopic endometriosis lesions from the peritoneum and ovaries, and tissue adjacent to endometriosis lesions in the peritoneum. In GSE179640, S1PR1 was specifically enriched in endothelial cells. It was significantly overexpressed in endothelial cells of ovarian endometriosis samples and in one of its myeloid cell clusters. Furthermore, upregulated expression of this gene was also detected in NK cells and a myeloid cell cluster of peritoneal endometriosis lesions and adjacent tissues. Figure 1B and 1C On the other hand, three sets of samples were available in GSE203191—menstrual discharge collected from individuals with endometriosis (diagnosed), symptomatic, and control. No significant LFC of S1PR1 was observed in case-control comparisons of any cell type.

[0097] S1PR1 agonists as candidates for reuse in endometriosis

[0098] Using PandaOmics' proprietary single-network model iPANDA, S1PR1 primarily facilitates immune regulatory pathways, through which most of these pathways are significantly activated in endometriosis samples. Figure 1D Literature has demonstrated the crucial role of S1PR1 and its ligand sphingosine-1-phosphate (S1P) in the immune response. Association information between S1PR1 variants and traits was retrieved from the GWAS catalog, and half of the traits were immune-related. Loss of S1PR1 function is lethal in mice. Conditional mutations in S1PR1 drive severe phenotypic abnormalities in the immune, cardiovascular, and neuronal systems (PMID: 22975327, 16314531, 12869509, 20584883, 21960637). S1PR1 has been reported to be upregulated in endometriosis (PMID: 30782093, 22277765). S1P increases IL-6 expression and the proliferative capacity of endometriotic cells (PMID: 30782093). Inhibition of S1PR1 and S1PR3 suppressed S1P-induced proliferation of endometriotic stromal cells (PMID: 30782093). S1P and its downstream pathways mediate the induction of COX-2 and PGE2 production, both important mediators of inflammation (PMID: 12890694, 26994820). Since endometriosis is a chronic inflammatory disease, and S1PR1 is closely associated with endometriosis, targeting S1PR1 could be a potential treatment for endometriosis.

[0099] Marketed S1PR1 agonists such as fingolimod, ciponimod, ozanimod, and bonesimod functionally antagonize the action of S1PR1 and are indicated for the treatment of multiple sclerosis. The binding of these compounds to S1PR1 induces receptor internalization and degradation. In particular, bonesimod specifically acts on the S1PR1 receptor. In addition to the marketed compounds, 16 other compounds have been engineered to target S1PR1 and tested on various endpoints, namely eltromod, ciponimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP1050, BMS520, BMS542, cirafimod, and PF-04629991.

Claims

1. A method for treating endometriosis in individuals in need, comprising administering an effective amount of a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist to said individual.

2. The method according to claim 1, wherein the S1PR1 antagonist is selected from one or more of the following: bonesimod, ozanimod, cibonimod, fingolimod, eltrimod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cirafimod, PF-04629991, and their derivatives.

3. Use of sphingosine-1-phosphate receptor 1 (S1PR1) antagonists in the preparation of medicaments for the treatment of endometriosis.

4. The use according to claim 3, wherein the S1PR1 antagonist is selected from one or more of the following: bonesimod, ozanimod, cibonimod, fingolimod, eltrimod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cirafimod, PF-04629991, and their derivatives.

5. A medication for the treatment of endometriosis, wherein the medication contains a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist.

6. The medicament for the stated use according to claim 5, wherein the S1PR1 antagonist is one or more of bonesimod, ozanimod, sibonimod, fingolimod, eltromod, sinimod, mokramod dihydrochloride, amiserol hydrochloride, CBP-307, TT-01688-CL, vibocilimod, icoplanin, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, cisrafimod, PF-04629991, and derivatives thereof.

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