Methods and compositions for treating diseases associated with inflammation, pain and / or lesions

Abstract

The technology described herein is directed to methods of administering an IL-8 receptor inhibitor to prevent, reduce, or treat inflammation, pain, and / or lesions. Compositions comprising a IL-8 receptor inhibitor are also described herein.

Description

METHODS AND COMPOSITIONS FOR TREATING DISEASES ASSOCIATED WITH INFLAMMATION, PAIN AND / OR LESIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 619,531 filed January 10, 2024, the contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The technology described herein relates to methods of treating diseases associated with inflammation, pain and / or lesions.BACKGROUND

[0003] Endometriosis is a painful inflammatory disease that affects up to 10% of individuals around the world with annual health care costs exceed $70 billion in the US alone. Current treatments for pain in endometriosis are limited to non-steroidal anti-inflammatory drugs (NSAIDs), other analgesics, hormonal agents, and surgical removal of the lesions. While effective for a fraction of patients, hormonal therapies and NSAIDs present several side effects, and should be used with cautious by patients with comorbidities. Moreover, even after surgery, disease and pain recurrence are very common and -15% of individuals experience no relief with any therapy, and up -30% experience recurrence of pain symptoms after treatment cessation. Therefore, new medical therapies and targets that provide long-term benefit are still required.

[0004] Data provided herein is show that in humans, IL-8 is a key mediator of inflammatory processes signaling through the IL-8 pathway. IL-8 receptors, CXCR1 and CXCR2, and their ligands for these receptors, CXCL1 / KC, CXCL2 / MIP-2, and CXCL5-6 / LIX, play important roles in inflammation. The effect of treatment has been examined with reparixin in a non- surgical mouse model of endometriosis. This model, therefore, can be used to screen novel or repurposed drugs for endometriosis treatment.SUMMARY

[0005] One aspect provided herein describes a method of preventing or reducing inflammation associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0006] In one embodiment of any aspect herein, the female reproductive organs include ovaries, fallopian tubes, uterus, uterosacral ligament, the peritoneum, and the peritoneal fluid surrounding the pelvis.

[0007] In one embodiment of any aspect herein, the inflammation is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0008] In one embodiment of any aspect herein, the inflammation is not associated with cancer of the female reproductive organs.

[0009] In one embodiment of any aspect herein, the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.

[0010] In one embodiment of any aspect herein, the inflammation is not associated with an ovarian cyst or uterine fibroids.

[0011] In one embodiment of any aspect herein, the inflammation is associated with endometriosis.

[0012] In one embodiment of any aspect herein, the inflammation is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0013] In one embodiment of any aspect herein, the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity.

[0014] In one embodiment of any aspect herein, the IL-8 receptor inhibitor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

[0015] In one embodiment of any aspect herein, the IL-8 receptor inhibitor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.

[0016] In one embodiment of any aspect herein, the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2. In one embodiment of any aspect herein, the IL-8 receptor is CXCR1. In one embodiment of any aspect herein, the IL-8 receptor is CXCR2.

[0017] In one embodiment of any aspect herein, the IL-8 receptor inhibitor is a small molecule inhibitor of IL-8 receptor. Exemplary small molecule inhibitor of IL-8 receptor include AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933. In one embodiment of any aspect herein, the small molecule inhibitor of IL-8 receptor is reparixin.

[0018] In one embodiment of any aspect herein, the administering is systemic or local administration.

[0019] In one embodiment of any aspect herein, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having inflammationassociated with female reproductive organs.

[0020] In one embodiment of any aspect herein, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having inflammation associated with female reproductive organs.

[0021] In one embodiment of any aspect herein, the subject has been previously treated for inflammation associated with female reproductive organs.

[0022] In one embodiment of any aspect herein, the subject has reoccurring inflammation associated with female reproductive organs.

[0023] In one embodiment of any aspect herein, the subject has acute inflammation associated with female reproductive organs.

[0024] In one embodiment of any aspect herein, the subject has chronic inflammation associated with female reproductive organs.

[0025] In one embodiment of any aspect herein, the method further comprises administering to a subject in need thereof a second therapeutic agent. Exemplary second therapeutic agents include a non-steroidal anti-inflammatory drug (NS AID), another analgesic, a hormonal agent, and surgical removal of a lesion(s).

[0026] In one embodiment of any aspect herein, the subject is a mammal. In one embodiment of any aspect herein, the subject is human.

[0027] Another aspect provided herein describes a method of preventing or reducing pain associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0028] In one embodiment of any aspect herein, the pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0029] In one embodiment of any aspect herein, the pain is not associated with cancer of the female reproductive organs.

[0030] In one embodiment of any aspect herein, the pain is not associated with an ovarian cyst or uterine fibroids.

[0031] In one embodiment of any aspect herein, the pain is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0032] In one embodiment of any aspect herein, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having pain associated with female reproductive organs.

[0033] In one embodiment of any aspect herein, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having pain associated with female reproductive organs.

[0034] In one embodiment of any aspect herein, the subject has been previously treated for pain associated with female reproductive organs.

[0035] In one embodiment of any aspect herein, the subject has reoccurring pain associated with female reproductive organs.

[0036] In one embodiment of any aspect herein, the subject has acute pain associated with female reproductive organs.

[0037] In one embodiment of any aspect herein, the subject has chronic pain associated with female reproductive organs.

[0038] In one embodiment of any aspect herein, the subject has spontaneous pain associated with female reproductive organs.

[0039] In one embodiment of any aspect herein, the subject has chronic and spontaneous pain associated with female reproductive organs.

[0040] Another aspect provided herein describes a method of preventing or treating at least one lesion on female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0041] In one embodiment of any aspect herein, the at least one lesion is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0042] In one embodiment of any aspect herein, the at least one lesion is not associated with cancer of the female reproductive organs.

[0043] In one embodiment of any aspect herein, the at least one lesion is not associated with an ovarian cyst or uterine fibroids.

[0044] In one embodiment of any aspect herein, the at least one lesion is associated with endometriosis.

[0045] In one embodiment of any aspect herein, the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0046] In one embodiment of any aspect herein, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion on female reproductive organs.

[0047] In one embodiment of any aspect herein, the method further comprises the step, priorto administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion on female reproductive organs.

[0048] In one embodiment of any aspect herein, the subject has been previously treated for at least one lesion associated with female reproductive organs.

[0049] In one embodiment of any aspect herein, the subject has reoccurring lesions associated with female reproductive organs.

[0050] In one embodiment of any aspect herein, the subject has acute lesions associated with female reproductive organs.

[0051] In one embodiment of any aspect herein, the subject has chronic lesions associated with female reproductive organs.

[0052] Another aspect provided herein describes a method of preventing or treating at least one lesion associated with endometriosis comprising administering an IL-8 receptor inhibitor to a subject in need thereof. In one embodiment of any aspect herein, the at least one lesion is present on or in any organ or tissue. In one embodiment of any aspect herein, the at least one lesion is present on the uterus, fallopian tubes, ovaries, intestines, rectum, bladder, uterosacral ligament, mesentery, peritoneum, liver, diaphragm, lungs, and / or surgical scar.

[0053] Another aspect provided herein describes a composition comprising an agent that inhibits an IL-8 receptor. In one embodiment of any aspect herein, the agent that inhibits IL-8 receptor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.

[0054] In one embodiment of any aspect herein, the agent that inhibits IL-8 receptor inhibits IL-8 receptor expression and / or activity.

[0055] In one embodiment of any aspect herein, IL-8 receptor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0056] In one embodiment of any aspect herein, the compositions further comprises a pharmaceutically acceptable carrier. In one embodiment of any aspect herein, the compositions further comprises a second therapeutic agent.

[0057] Another aspect provided herein describes a method of treating or preventing inflammation, pain, or at least one lesion, the method comprising administering any of the compositions described herein to a subject in need thereof.

[0058] In one embodiment of any aspect herein, the subject has or is at risk of having inflammation, pain, or lesions. In one embodiment of any aspect herein, the subject does not have cancer of the female reproductive organs. In one embodiment of any aspect herein, thesubject does not have an ovarian cyst or uterine fibroids.

[0059] Another aspect provided herein describes a use of any of the compositions described herein for the treatment or prevention of inflammation, pain or lesions.

[0060] Another aspect provided herein describes a method of treating or preventing at least one lesion associated with endometriosis, the method comprising administering an IL-8 receptor inhibitor to a subject in need thereof, wherein the IL-8 receptor inhibitor is reparixin. Definitions

[0061] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed technology, because the scope of the technology is limited only by the claims. 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 technology belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0062] Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, 2014 (ISBN 0815345305, 9780815345305);Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E.Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are all incorporated by reference herein in their entireties.

[0063] As used herein, the terms "treat,” "treatment," "treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with inflammation of the female reproductive organs (e.g., endometriosis). The term “treating" includes reducing or alleviating at least one adverse effect or symptom of inflammation of the female reproductive organs (e.g., endometriosis) for example, lesions and / or pain from the female reproductive organs. Treatment is generally “effective" if one or more signs, symptoms, or clinical markers are reduced. Alternatively, treatment is “effective" if the progression of a disease or disorder is reduced or halted. That is, “treatment" includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and / or decreased morbidity and / or mortality, whether detectable or undetectable. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[0064] As used herein "preventing" or "prevention" refers to any methodology where the disease state does not occur due to the actions of the methodology (such as, for example, administration of an agent as described herein). In one aspect, it is understood that prevention can also mean that the disease is not established to the extent that occurs in untreated controls. Accordingly, prevention of a disease encompasses a reduction in the likelihood that a subject can develop the disease, relative to an untreated subject (e.g., a subject who is not treated with the methods or compositions described herein).

[0065] As used herein, the terms "administering," and "injecting" are used interchangeably in the context of the placement of an agent (e.g., a small molecule) described herein, into a subject, by a method or route which results in at least partial localization of the agent at a desired site, such as the female reproductive organs or a region thereof, such that a desired effect(s) is produced (e.g., reduction or elimination of pain, lesions, adhesions, and / or inflammation). The agent described herein can be administered by any appropriate routewhich results in delivery to a desired location in the subject. The half-life of the agent after administration to a subject can be as short as a few minutes, hours, or days, e.g., twenty -four hours, to a few days, to as long as several years, i.e., long-term. In some embodiments of any of the aspects, the term “administering” refers to the administration of a pharmaceutical composition comprising one or more agents. The administering can be done by direct injection (e.g., directly administered to a target cell or tissue), subcutaneous injection, muscular injection, oral, or nasal delivery to the subject in need thereof. Administering can be local or systemic.

[0066] The terms “patient”, “subject” and “individual” are used interchangeably herein, and refer to an animal, particularly a human, to whom treatment, including prophylactic treatment is provided. The term “subject” as used herein refers to human and non-human animals. The term “non-human animals” and “non-human mammals” are used interchangeably herein includes all vertebrates, e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent (e.g., mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, and non-mammals such as chickens, amphibians, reptiles etc. In one embodiment of any of the aspects, the subject is human. In another embodiment, of any of the aspects, the subject is an experimental animal or animal substitute as a disease model. In another embodiment, of any of the aspects, the subject is a domesticated animal including companion animals (e.g., dogs, cats, rats, guinea pigs, hamsters etc.). A subject can have previously received a treatment for inflammation of the female reproductive organs (e.g., endometriosis), or has never received treatment for inflammation of the female reproductive organs (e.g., endometriosis). A subject can have previously been diagnosed with having inflammation of the female reproductive organs (e.g., endometriosis), or has never been diagnosed with inflammation of the female reproductive organs (e.g., endometriosis).

[0067] The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease or lessening of a property, level, or other parameter by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, “reduction” or “inhibition” does not encompass a complete inhibition or reduction ascompared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0068] The terms “increased," “increase," “increases,” or “enhance" or “activate" are all used herein to generally mean an increase of a property, level, or other parameter by a statistically significant amount; for the avoidance of any doubt, the terms “increased", “increase" or “enhance" or “activate" means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5 -fold or at least about a 10-fold increase, at least about a 20-fold increase, at least about a 50-fold increase, at least about a 100-fold increase, at least about a 1000-fold increase or more as compared to a reference level. For example, increasing activity can refer to increased numbers of lesions of the female reproductive organs (e.g., endometriosis), increased pain of the female reproductive organs (e.g., endometriosis), or increasing levels of inflammation of the female reproductive organs (e.g., endometriosis), directly or indirectly.

[0069] As used herein, a “reference level” refers to a normal, otherwise unaffected cell population or tissue (e.g., a biological sample obtained from a healthy subject, or a biological sample obtained from the subject at a prior time point, e.g., a biological sample obtained from a patient prior to being diagnosed with inflammation of the female reproductive organs (e.g., endometriosis), or a biological sample that has not been contacted with an agent or composition disclosed herein).

[0070] As used herein, an “appropriate control” refers to an untreated, otherwise identical cell or population (e.g., a biological sample that was not contacted by an agent or composition described herein, or not contacted in the same manner, e.g., for a different duration, as compared to a non-control cell).

[0071] The term "pharmaceutically acceptable" can refer to agents and compositions which can be administered to a subject (e.g., a mammal or a human) without undue toxicity.

[0072] As used herein, the term “pharmaceutical composition” or "pharmaceutically acceptable carrier" are used interchangeably and can include any material or substance that, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limitedto, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, emulsions such as oil / water emulsion, and various types of wetting agents. The term “pharmaceutically acceptable carriers" excludes tissue culture media. Non limiting examples of pharmaceutical carriers include particle or polymer-based vehicles such as nanoparticles, microparticles, polymer microspheres, or polymer-drug conjugates.

[0073] As used herein, a "subject" means a human or animal, for example, a mammal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include, for example, chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include, for example, mice, rats, woodchucks, rabbits and hamsters. Domestic and game animals include, for example, cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “individual,” “patient” and “subject” are used interchangeably herein.

[0074] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that provide animal models of disease e.g., cardiac disease or disorder, such as muscular dystrophy. A subject can be male or female.

[0075] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e.g., endometriosis) or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having such condition or related complications. For example, a subject can be one who exhibits one or more risk factors for the condition, or one or more complications related to the condition or a subject who does not exhibit risk factors.

[0076] A “subject in need” of treatment for a particular condition can be a subject having that condition (e.g., endometriosis), diagnosed as having that condition, or at risk of developing that condition.

[0077] The term “statistically significant" or “significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.

[0078] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understoodas modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean ±1%.

[0079] As used herein, the term “comprising” means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation.

[0080] The term "consisting of' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0081] As used herein the term "consisting essentially of' refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the technology.

[0082] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g.," is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g.," is synonymous with the term "for example."

[0083] As used herein, the term “inflammation” or “inflamed” refers to activation or recruitment of the immune system or immune cells (e.g., T cells, B cells, neutrophils, NK cells, granulocytes, macrophages). A tissue that has inflammation can become reddened, white, swollen, hot, painful, exhibit a loss of function, or have a film or mucus. Immune cells may secrete cytokines and interferons to signal other immune cells and promote phagocytosis of the microorganism and infected cells. Methods of identifying inflammation are well known in the art. Inflammation typically occurs following injury or infection by a microorganism. Inflammation can result in the release of cytokines by T cells. These cytokines are known to have various effects on the immune response and target tissues (e.g., female reproductive organs or sensory nerves).

[0084] As used herein, the term “cytokine” refers to a small protein (-5-20 kDa) that acts through a target cytokine receptor to modulate the immune response, cell growth, or other cellular functions.

[0085] As used herein, the term “interleukin-8 receptor” or “IL-8 receptor” refers to an interleukin-8 receptor that is expressed on neutrophils. Specifically, IL-8 receptors canregulate activation of neutrophils, allowing for the recruiting of more inflammatory cells to the site of IL-8 release and to produce enzymes that would assist in the destruction of foreign material at the site of infection. There are two known IL-8 receptors, IL-8 receptor A or CXCR1 and IL-8 receptor B or CXCR2. These names can be used interchangeably throughout the application. Sequences for CXCR1 are known for a number of species, e.g., human CXCR1 (NCBI GenelD: 3577) polypeptide and mRNA (e.g., NCBI Reference Sequences: NM_000634.3 and NP 000625.1). CXCR1 can refer to human CXCR1, including naturally occurring variants, molecules, genetically engineered CXCR1, and alleles thereof. CXCR1 refers to the mammalian CXCR1 of, e.g., mouse, rat, rabbit, dog, cat, cow, horse, pig, and the like. The amino acid sequence of human CXCR1 is shown in SEQ ID NO: 2 for the mRNA and SEQ ID NO: 3 for the protein.

[0086] Sequences for CXCR2 are known for a number of species, e.g., human CXCR2 (NCBI GenelD: 3579) polypeptide and mRNA (e.g., NCBI Reference Sequences: NM_001168298.2, NM_001557.4, NP_001161770.1, and NP_001548.1). CXCR2 can refer to human CXCR2, including naturally occurring variants, molecules, genetically engineered CXCR2, and alleles thereof. CXCR2 refers to the mammalian CXCR2 of, e.g., mouse, rat, rabbit, dog, cat, cow, horse, pig, and the like. The amino acid sequence of human CXCR2 is shown in SEQ ID NO: 5 and SEQ ID NO: 6 for the mRNA and SEQ ID NO: 7 and SEQ ID NO: 8 for the protein.

[0087] As used herein, a “lesion” refers to the growth of tissue in an abnormal location or any damage or abnormal change in the tissue of an organism as compared to wild-type tissue, usually caused by disease or injury. A lesion can occur at, but not limited to, the bladder, small intestine, large intestine, diaphragm, liver, lung, skin (especially at the site of surgical scars (e.g., Cesarean-section scars and / or umbilical scars (i.e., belly button), and female reproductive organs. Lesions can arise, e.g., as the result of a disease of the female reproductive organs (e.g., ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis), but do not necessarily need to arise or remain in the female reproductive organs.

[0088] As used herein, a “cancer of the female reproductive organs” refers to any cancer that arises in the female reproductive organs including, but not limited to uterine cancer, ovarian cancer, Fallopian tube cancer, cervical cancer, vaginal cancer, and vulvar cancer. The cancer can be benign, malignant, or metastatic, and at any stage.

[0089] As used herein, an “ovarian remnant” refers to the removal of one or more ovaries and ovarian tissues still remains after the surgery or oophorectomy, resulting in, e.g., thedevelopment of a pelvic mass, pelvic pain, and painful sexual intercourse. Signs and symptoms include pelvic pain, a pelvic mass, or the absence of menopause after surgery. Risk factors include, but are not limited to adhesions in the tissue, anatomic variations, intraoperative bleeding, and poor surgical technique.

[0090] As used herein, “pelvic pain syndrome” refers to chronic pain in the pelvic area that lasts more than six months. Causes include, but are not limited to pregnancy, endometriosis, bowel adhesions, irritable bowel syndrome, and interstitial cystitis.

[0091] As used herein, “chronic pelvic inflammatory disease” refers to an infection of the upper part of the female reproductive system, including but not limited to the uterus, fallopian tubes, ovaries, and the inside of the pelvis. Sometimes there can be no symptoms. Other times, signs and symptoms can include, but are not limited to lower abdominal pain, vaginal discharge, fever, burning with urination, pain with sex, bleeding after sex, or irregular menstruation.

[0092] As used herein, “adenomyosis” refers to a condition where the inner lining of the uterus or the endometrium grows into the muscle wall of the uterus, resulting in painful and heavy menstrual bleeding. Symptoms can include, but are not limited to painful menstrual cycles, heavy menstrual cycles, pain during sexual intercourse, chronic pelvic pain, and irritation of the urinary bladder.

[0093] As used herein, “uterine fibroids”, “uterine leiomyomas”, or “fibroids” refer to benign smooth muscle tumors of the uterus. Sometimes, no symptoms are present. Other times, symptoms can include painful or heavy menstrual cycles, frequent urination, pain during sexual intercourse, or lower back pain. At least one or more uterine fibroids can be present on the uterus.

[0094] As used herein, “reoccurring inflammation” or “reoccurring pain” refers to inflammation or pain that occurs either due to a known stimulus or unknown stimulus and occurs again at a later time. The inflammation or pain is non-continuous.

[0095] As used herein, “acute inflammation” or “acute pain” refers to inflammation or pain of recent onset. Usually, the source of the inflammation or pain can be readily identified and managed.

[0096] As used herein, “chronic inflammation" or “chronic pain” refers to inflammation that occurs continuously over a longer period of time, for example, at least 1 week, at least 1 month, at least 1 year, etc.

[0097] As used herein, “spontaneous pain” refers to pain that occurs suddenly and has no known stimulus or cause.BRIEF DESCRIPTION OF THE DRAWINGS

[0098] FIGs. 1A-1D. FIG. 1A shows the percentage of mice with visible lesions were determined by a simple count of the visable lesions in mice. Results are expressed as percentage (%) of mice with lesions; Mantel-Cox method followed by the logrank test. FIG. IB examines the lesion size, which was determined by measuring height and width, *p<0.05 vs vehicle. FIG. 1C shows the number of lesions per mouse was also determined by a simple count of the how many lesions were found in the mouse. FIG. ID examines how lesion burden was determined by summing the size of all lesions present in each mouse. Results are expressed as mean ± SEM of % change.

[0099] FIGs. 2A-2C shows the effect of reparixin on endometriosis-associated changes in thermal selection. FIG. 2A shows the heat map of the time spent (in seconds) for each mouse in each of the temperature zones in the thermal gradient assay. Results are expressed as time spent in each zone (in sec). FIG. 2B contains a group mean heat map which shows the mean time spent in each of the temperature zones in the thermal gradient assay. Results are expressed as mean of time spent in each zone. FIG. 2C shows these data as an x-y line plot.

[0100] FIG. 3A-3C shows the effect of reparixin on endometriosis-induced spontaneous pain. FIG. 3A examines the number of abdominal contortions, which consists of a contraction of the abdominal muscle together with stretching of hind limbs. FIG. 3B determines for abdominal squashing, which was quantified the number of times the mice pressed the lower abdominal region against the cage floor. FIG. 3C determines for direct abdominal licking, which was quantified the total number of times that mice directly groomed the abdominal region (without going for any other body region before or after the behavior). Results are expressed as mean ± SEM of measurement, * p <0.05, ** p<0.005, ***p<0.001.

[0101] FIG. 4 shows the effect of reparixin on endometriosis-associated mechanical pain. Mechanical abdominal pain was determined weekly, 7 to 56 dpi using von Frey filaments. Data was plotted weekly. Results are expressed as mean ± SEM of measurements,* p <0.05.DETAILED DESCRIPTION

[0102] The technology described herein refers to the methods and compositions used to treat and / or prevent inflammation, pain, and lesions associated with a disease of the female reproductive organs (i.e., endometriosis), comprising of administering an IL-8 receptor inhibitor to a subject in need thereof. One aspect provided herein provides a method ofpreventing or reducing inflammation associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof. Another aspect provided herein is a method of preventing or reducing pain associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof. Another aspect as provided herein is method of preventing or treating at least one lesion on female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.Treating or Preventing Inflammation

[0103] One aspect as described herein is a method of preventing or reducing inflammation associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0104] In one embodiment, the female reproductive organs include ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis.

[0105] In one embodiment, the inflammation or pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0106] In a preferred embodiment, the inflammation is associated with endometriosis.

[0107] In one embodiment, the inflammation is not associated with cancer of the female reproductive organs. The cancer of the female reproductive organs can include uterine cancer or ovarian cancer.

[0108] In another embodiment, the inflammation is not associated with an ovarian cyst or uterine fibroids.

[0109] As used herein, the term “inflammation” or “inflamed” or “inflammatory” refers to activation or recruitment of the immune system or immune cells (e.g., T cells, B cells, macrophages). A tissue that has inflammation can become, for example, reddened, white, swollen, hot, painful, exhibit a loss of function, or have a film or mucus. Methods of identifying inflammation are well known in the art and can be assessed by a skilled clinician. Inflammation can occur following injury, aberrant tissue growth, or infection by a microorganism. Inflammation can also occur following aberrant activation of one or multiple pro-inflammatory signaling pathways. Examples of pro-inflammatory signaling pathways and cytokines include TNF, IL-6, IL-1, and IL-8. In some embodiments, inflammation can occur upon activation of the IL-8 receptors CXCR1 and / or CXCR2.

[0110] There are different types of inflammation, including acute inflammation, chronic inflammation, and reoccurring inflammation. Acute inflammation can occur immediately after injury and last for up to two weeks. Chronic inflammation can occur and last for months or years when acute inflammation fails to settle. The transition from acute to chronic inflammation is also known as subacute inflammation, which can last from 2 to 6 weeks. Additional information can be found in Hannoodee and Hasuruddin, 2022. In some embodiments, the subject has reoccurring inflammation associated with female reproductive organs. In some embodiments, the subject has acute inflammation associated with female reproductive organs. In other embodiments, the subject has chronic inflammation associated with female reproductive organs.

[0111] In one embodiment, the inflammation is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0112] In one embodiment, the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity. For example, the IL-8 receptor inhibitor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

[0113] Inflammation can occur at least 1 day after initial onset, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 31 days, at least 32 days, at least 33 days, at least 34 days, at least 35 days, at least 36 days, at least 37 days, at least 38 days, at least 39 days, at least 40 days, at least 41 days, at least 42 days, at least 43 days, at least 44 days, at least 45 days, at least 46 days, at least 47 days, at least 48 days, at least 49 days, at least 50 days, at least 51 days, at least 52 days, at least 53 days, at least 54 days, at least 55 days, at least 56 days, at least 57 days, at least 58 days, at least 59 days, at least 60 days, at least 61 days, at least 62 days, at least 63 days, at least 64 days, at least 65 days, at least 66 days, at least 67 days, at least 68 days, at least 69 days, at least 70 days, at least 71 days, at least 72 days, at least 73 days, at least 74 days, at least 75 days, at least 76 days, at least 77 days, at least 78 days, at least 79 days, at least 80 days, at least 81 days, at least 82 days, at least 83 days, at least 84days, at least 85 days, at least 86 days, at least 87 days, at least 88 days, at least 89 days, at least 90 days, at least 91 days, at least 92 days, at least 93 days, at least 94 days, at least 95 days, at least 96 days, at least 97 days, at least 98 days, at least 99 days, at least 100 days, at least 101 days, at least 102 days, at least 103 days, at least 104 days, at least 105 days, at least 106 days, at least 107 days, at least 108 days, at least 109 days, at least 110 days, at least 111 days, at least 112 days, at least 113 days, at least 114 days, at least 115 days, at least 116 days, at least 117 days, at least 118 days, at least 119 days, at least 120 days or more.

[0114] Acute inflammation can occur between 1 day and 14 days after initial onset, between 2 days and 14 days, between 3 days and 14 days, between 4 days and 14 days, between 5 days and 14 days, between 6 days and 14 days, between 7 days and 14 days, between 8 days and 14 days, between 9 days and 14 days, between 10 days and 14 days, between 11 days and 14 days, between 12 days and 14 days, between 13 days and 14 days. Acute inflammation can occur less than one day after initial onset. Acute inflammation can be non-continuous. Acute inflammation can arise from acute or spontaneous pain.

[0115] Chronic inflammation can occur between 15 days and 120 days, between 20 days and 120 days, between 25 days and 120 days, between 30 days and 120 days, between 35 days and 120 days, between 40 days and 120 days, between 45 days and 120 days, between 50 days and 120 days, between 55 days and 120 days, between 60 days and 120 days, between 65 days and 120 days, between 70 days and 120 days, between 75 days and 120 days, between 80 days and 120 days, between 85 days and 120 days, between 90 days and 120 days, between 95 days and 120 days, between 100 days and 120 days, between 105 days and 120 days, between 110 days and 120 days, between 115 days and 120 days. Chronic inflammation can occur longer than 120 days. Chronic inflammation can arise from acute or spontaneous inflammation.

[0116] In some embodiments, the subject has been previously treated for inflammation associated with female reproductive organs.

[0117] In some embodiments, the subject has reoccurring inflammation associated with female reproductive organs. In some embodiments, the subject has acute inflammation associated with female reproductive organs. In some embodiments, the subject has chronic inflammation associated with female reproductive organs.

[0118] In one embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having inflammation associated with female reproductive organs.

[0119] In one embodiment, the method further comprises the step, prior to administering,receiving the results of an assay that diagnoses the subject of having or at risk of having inflammation associated with female reproductive organs.

[0120] Treating or Preventing Pain

[0121] Another aspect as described herein is a method of preventing or reducing pain associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0122] In one embodiment, the female reproductive organs include ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis.

[0123] In one embodiment, the pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0124] In a preferred embodiment, the pain is associated with endometriosis.

[0125] In one embodiment, the pain is not associated with cancer of the female reproductive organs. The cancer of the female reproductive organs can include uterine cancer or ovarian cancer.

[0126] In another embodiment, the pain is not associated with an ovarian cyst or uterine fibroids.

[0127] In one embodiment, the pain is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0128] In one embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having pain associated with female reproductive organs.

[0129] In one embodiment, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having pain associated with female reproductive organs.

[0130] In one embodiment, the subject has been previously treated for pain associated with female reproductive organs.

[0131] In one embodiment, the subject has reoccurring pain associated with female reproductive organs.

[0132] In one embodiment, the subject has acute pain associated with female reproductive organs.

[0133] In one embodiment, the subject has chronic pain associated with female reproductive organs.

[0134] In one embodiment, the subject has spontaneous pain associated with female reproductive organs.

[0135] In one embodiment, the subject has chronic and spontaneous pain associated with female reproductive organs.Treating or Preventing Lesions

[0136] Another aspect as described herein is a method of preventing or reducing at least one lesion associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

[0137] Another aspect herein provides a method of preventing or treating at least one lesion associated with endometriosis comprising administering an IL-8 receptor inhibitor to a subject in need thereof. In one embodiment of this or any aspect, the at least one lesion is present on or in any organ or tissue. In one embodiment of this or any aspect, the at least one lesion is present on the uterus, fallopian tubes, ovaries, intestines, rectum, bladder, uterosacral ligament, mesentery, peritoneum, liver, diaphragm, lungs, and / or surgical scar.

[0138] The at least one lesion can be one lesion, or it can be more than one lesion. For example, the at least at least 3 lesions, at least 4 lesions, at least 5 lesions, at least 6 lesions, at least 7 lesions, at least 8 lesions, at least 9 lesions, at least 10 lesions, at least 11 lesions, at least 12 lesions, at least 13 lesions, at least 14 lesions, at least 15 lesions, at least 16 lesions, at least 17 lesions, at least 18 lesions, at least 19 lesions, at least 20 lesions, at least 21 lesions, at least 22 lesions, at least 23 lesions, at least 24 lesions, at least 25 lesions, at least 26 lesions, at least 27 lesions, at least 28 lesions, at least 29 lesions, at least 30 lesions, at least 31 lesions, at least 32 lesions, at least 33 lesions, at least 34 lesions, at least 35 lesions, at least 36 lesions, at least 37 lesions, at least 38 lesions, at least 39 lesions, at least 40 lesions, at least 41 lesions, at least 42 lesions, at least 43 lesions, at least 44 lesions, at least 45 lesions, at least 46 lesions, at least 47 lesions, at least 48 lesions, at least 49 lesions, at least 50 lesions, at least 51 lesions, at least 52 lesions, at least 53 lesions, at least 54 lesions, at least 55 lesions, at least 56 lesions, at least 57 lesions, at least 58 lesions, at least 59 lesions, at least 60 lesions, at least 61 lesions, at least 62 lesions, at least 63 lesions, at least 64 lesions, at least 65 lesions, at least 66 lesions, at least 67 lesions, at least 68 lesions, at least 69 lesions, at least 70 lesions, at least 71 lesions, at least 72 lesions, at least 73 lesions,at least 74 lesions, at least 75 lesions, at least 76 lesions, at least 77 lesions, at least 78 lesions, at least 79 lesions, at least 80 lesions, at least 81 lesions, at least 82 lesions, at least 83 lesions, at least 84 lesions, at least 85 lesions, at least 86 lesions, at least 87 lesions, at least 88 lesions, at least 89 lesions, at least 90 lesions, at least 91 lesions, at least 92 lesions, at least 93 lesions, at least 94 lesions, at least 95 lesions, at least 96 lesions, at least 97 lesions, at least 98 lesions, at least 99 lesions, at least 100 lesions, or more.

[0139] The more than one lesion can be present on the same organ or tissue. Alternatively, if more than one lesion is present, they need not be located on the same location (i.e., organ or tissue). For example, the subject can have one lesion on an ovary and one lesion on the bladder.

[0140] In one embodiment, the female reproductive organs include ovaries, fallopian tubes, uterus, the peritoneum, uterosacral ligament, and the peritoneal fluid surrounding the pelvis.

[0141] In one embodiment, the at least one lesion is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

[0142] In a preferred embodiment, the at least one lesion is associated with endometriosis.

[0143] In one embodiment, the at least one lesion is not associated with cancer of the female reproductive organs. The cancer of the female reproductive organs can include uterine cancer or ovarian cancer.

[0144] In another embodiment, the at least one lesion is not associated with an ovarian cyst or uterine fibroids.

[0145] In one embodiment, the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0146] In one embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion associated with female reproductive organs.

[0147] In one embodiment, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion associated with female reproductive organs.

[0148] In one embodiment, the subject has been previously treated for a lesion(s) associated with female reproductive organs.

[0149] In one embodiment, the subject has reoccurring lesion associated with female reproductive organs.

[0150] In one embodiment, the subject has acute lesion associated with female reproductive organs.

[0151] In one embodiment, the subject has chronic lesion associated with female reproductive organs.

[0152] In one embodiment, the subject has spontaneous lesion associated with female reproductive organs.

[0153] In one embodiment, the subject has chronic and spontaneous lesion associated with female reproductive organs.Endometriosis

[0154] Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside of the uterus. One characteristic of endometriosis is lesions. Lesions can be found on ovaries, fallopian tubes, tissue around the uterus and ovaries, intestines, bladder, and diaphragm.

[0155] Symptoms of endometriosis include, but are not limited to, pelvic pain (both acute and chronic pain), heavy and painful periods, pain with bowel movements, painful urination, pain during sexual intercourse and infertility. Risk factors can include having a family history of the disease, environmental toxins such as prolonged exposure to estrogen or obstruction of menstrual outflow, and vaginal dysbiosis, an imbalance in the vaginal microbiome and the appearance of endometriosis.

[0156] Pelvic pain can range from mild to severe cramping or stabbing pain occurring on both sides of the pelvis, in the lower back and rectal area, and down the legs. Pain can start a week before a menstrual period, during a menstrual period, and a week after a menstrual period. Pain can be constant. Pain can be unrelated to the menstrual period. Symptoms of endometriosis-related pain can also include dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, mittelschmerz, and bodily movement pain. Additional causes include hormonal stimulation of lesion and organ dislocation that arises for adhesion binding internal organs to each other (i.e., binding of the ovaries, uterus, oviducts, peritoneum, and / or bladder to each other).Endometrioma

[0157] Endometrioma is the presence of tissue similar to, but distinct from, the endometrium in and sometimes on the ovary. Endometrial tissue is the mucous membranethat normally lines the uterus. When an endometrioma forms, it can produce a toxic environment comprising estrogen, cytokines, interleukins, and other inflammatory substances that can damage healthy ovarian tissue. Endometrioma can also be known as a chocolate cyst, due to the color of the fluid that fills the cyst. Unlike an ovarian cyst, endometrioma is a nonfunctional cyst where hormone is not produced by the cyst.

[0158] Endometriomas indicate a more severe disease state in patients with endometriosis. Symptoms of endometriomas include, but are not limited to pelvic pain, heavy menstrual period, painful menstrual period, back pain, painful sexual intercourse, painful urination, painful bowel movements, change in urinary frequency, nausea, vomiting, and bloating.Treating or Preventing Endometriosis

[0159] Treatment or prevention of endometriosis can include the targeting of an IL-8 receptor such as CXCR1 and / or CXCR2 with an IL-8 receptor inhibitor. In some embodiments, the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity.

[0160] The IL-8 receptor inhibitor expression and / or activity can be inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

[0161] In some embodiments, inflammation can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

[0162] In some embodiments, the subject has been previously treated for inflammation associated with female reproductive organs.

[0163] Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside of the uterus. One characteristic of endometriosis is lesions. Lesions can be found on, for example, uterus, fallopian tubes, ovaries, intestines, rectum, bladder, uterosacral ligament, mesentery, peritoneum, liver, diaphragm, lungs, and / or surgical scar. Symptoms of endometriosis include, but are not limited to, pelvic pain (both acute and chronic pain), heavy and painful periods, pain with bowel movements, painful urination, pain during sexual intercourse and infertility. Risk factors can include having a family history of the disease, environmental toxins such as prolonged exposure to estrogen or obstruction of menstrual outflow, and vaginal dysbiosis, an imbalance in the vaginal microbiome and the appearance of endometriosis.

[0164] Pelvic pain can range from mild to severe cramping or stabbing pain occurring on both sides of the pelvis, in the lower back and rectal area, and down the legs. Pain can start a week before a menstrual period, during a menstrual period, and a week after a menstrual period. Pain can be constant. Symptoms of endometriosis-related pain can also include dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, mittelschmerz, and bodily movement pain. Additional causes include hormonal stimulation of lesion and organ dislocation that arises for adhesion binding internal organs to each other (i.e., binding of the ovaries, uterus, oviducts, peritoneum, and / or bladder to each other).Treating or Preventing Vaginal Dysbiosis

[0165] Treatment or prevention of vaginal dysbiosis can include the targeting of an IL-8 receptor such as CXCR1 and / or CXCR2 with an IL-8 receptor inhibitor. In some embodiments, the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity.

[0166] The IL-8 receptor inhibitor expression and / or activity can be inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

[0167] In some embodiments, inflammation can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control. Lactobacillus bacteria can be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration. The polymicrobial biofilm on vaginal epithelial cells can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

[0168] Vaginal dysbiosis is a term for imbalance or maladaptation of bacterial communities in the vagina. For example, a vaginal microbiome that is not dominated by lactobacilli. The different types of vaginal dysbiosis include, but are not limited to bacterial vaginosis (BV) and cytolytic vaginosis (CyV).

[0169] Bacterial vaginosis (BV) is a polymicrobial disorder, where the ratio of Lactobacillus genus is much lower compared to a subject not diagnosed with BV. Additional species of bacteria can be found in higher abundance in the vaginal microbiome in a subject diagnosed with BV as compared to a subject not diagnosed, including but not limited toGardnerella vaginalis, Atopobium vaginae, Megasphaera types, Leptotrichia amnionii, Sneathia sanguinegens, Porphyromonas asaccharolytica, a bacterium related to Eggerthella hongkongensis, and bacteria related to Prevotella generum. BV is also characterized by the presence of a polymicrobial biofilm on vaginal epithelial cells. The reduced abundance of Lactobacillus genus in the vaginal environment leads to elevated levels of proinflammatory cytokines, a compromised immunosurveillance system, and altered immune cell profiles. The secretion of pro-inflammatory cytokines (i.e., IL-8) promotes the proliferation and adhesion of endometrial cells. Additional information about vaginal dysbiosis and BV can be found in Lev-Sagie et al. 2022 Vaginal Dysbiotic Conditions. J Low Genit Tract Dis. 2022 Jan l;26(l):79-84; Jiang I, Yong PJ, Allaire C, Bedaiwy MA. Intricate Connections between the Microbiota and Endometriosis. Int J Mol Sci. 2021 May 26;22(11):5644; and Khan KN, Fujishita A, Hiraki K, Kitajima M, Nakashima M, Fushiki S, Kitawaki J. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018 Jan 18; 17(2): 125-133.IL-8 Receptors Inhibitors

[0170] In various embodiments, the IL-8 receptor inhibitor is an antibody reagent, an inhibitory nucleic acid, or a small molecule. In one embodiment, the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2.

[0171] Interleukin-8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells, and endothelial cells. The biological activity of IL8 is mediated by the interaction with two receptors, CXCR1 and CXCR2, belonging to the 7TM-GPCR family, that are expressed on the surface of human PMNs. Alternative terms to refer to CXCR1 include IL-8 receptor alpha, CMKAR1, CKR-1, CDwl28a, and CD181. Alternative terms to refer to CXCR2 include IL-8 receptor beta, CD182, CMKAR2, CDwl28b, and CKR-2.

[0172] CXCR1 and CXCR2 are closely related integral membrane proteins that recognize CXC chemokines that possess an E-L-R amino acid motif next to their CXC motif. CXCR1 can recognize IL-8 and CXCL6. CXCR2 can recognize CXCL1 and CXCL7. CXCR1 and CXCR2 are expressed on the surface of neutrophils in mammals. CXCR1 and CXCR2 have implicated in a variety of diseases, such as cancer, lung disease, and autoimmune diseases, such as inflammatory bowel disease and rheumatoid arthritis. Additional description can be found in Moepps, 2015.

[0173] CXCR1 referred to in this aspect, and all aspects and embodiments described hereinin this application, comprises the nucleotide sequences of CXCR1 with NCBI nucleotide sequence IDs: NG_011814.1 (SEQ ID NO: 1), NM_000634.3 (SEQ ID NO: 2), and NP_000625.1 (SEQ ID NO: 3).

[0174] CXCR2 referred to in this aspect, and all aspects and embodiments described herein in this application, comprises the nucleotide sequences of CXCR2 with NCBI nucleotide sequence IDs: NG_052975.1 (SEQ ID NO: 4), NM_001168298.2 (SEQ ID NO: 5), NM_001557.4 (SEQ ID NO: 6), NP_001161770.1 (SEQ ID NO: 7), and NP_001548.1 (SEQ ID NO: 8)

[0175] In one embodiment, the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2. In one embodiment, the IL-8 receptor is CXCR1. In another embodiment, the IL-8 receptor is CXCR2.

[0176] In some embodiments the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity. The IL-8 receptor inhibitor expression and / or activity can be inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration. In some embodiments, the IL-8 receptor inhibitor is an inhibitory nucleic acid, an antibody reagent, or a small molecule.

[0177] Inhibitory Nucleic Acid

[0178] In some embodiments of any of the aspects, the agent that inhibits an IL-8 receptor is an inhibitory nucleic acid. In some embodiments of any of the aspects, inhibitors of the expression of a given gene can be an inhibitory nucleic acid. As used herein, “inhibitory nucleic acid” refers to a nucleic acid molecule which can inhibit the expression of a target, e.g., double-stranded RNAs (dsRNAs), inhibitory RNAs (iRNAs), and the like. In some embodiments of any of the aspects, the inhibitory nucleic acid can be a silencing RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA). Inhibitory nucleic acids can also include guide sequence molecules (e.g., a guide RNA) that function, e.g., in combination with an enzyme, to induce insertions, deletions, indels, and / or mutations of a target, thereby inhibiting the expression of the target.

[0179] Generally, a nucleic acid inhibitor comprises a nucleotide sequence that is substantially complementary to at least a portion of a nucleic acid encoding an IL-8 receptor (e.g., CXCR1 and CXCR2). For example, the nucleic acid inhibitor comprises a nucleotide sequence that is substantially complementary to at least a portion of a nucleotide sequence selected from SEQ ID NOs: 1-8 In some embodiments, the nucleic acid inhibitor comprisesa nucleotide sequence that is substantially complementary to at least a portion of a nucleotide sequence selected from SEQ ID NOs: 1-2, SEQ ID NOs: 4-6.

[0180] In some embodiments of any of the aspects, the nucleic acid inhibitor comprises a sequence at least 15 nucleotides in length that is substantially complementary to at least a portion of a nucleotide sequence selected from SEQ ID NOs: 1-8. For example, the nucleic acid inhibitor comprises a sequence 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length that is substantially complementary to at least a portion of a nucleotide sequence selected from SEQ ID NOs: 1-8

[0181] In some embodiments, the nucleic acid inhibitor inhibits an IL-8 receptor (e.g., CXCR1 and CXCR2). For example, the nucleic acid inhibitor comprises a sequence 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length that is substantially complementary to at least a portion of a nucleotide sequence selected from SEQ ID NOs: 1-8.

[0182] In some embodiments of any of the aspects, an iNA comprises a sequence that is complementary to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 15 nucleotides in length that is complementary to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 20 nucleotides in length that is complementary to at least a portion of a target sequence described herein.

[0183] In some embodiments of any of the aspects, an iNA comprises a sequence that is the reverse complement to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 15 nucleotides in length that is the reverse complement to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 20 nucleotides in length that is the reverse complement to at least a portion of a target sequence described herein.

[0184] In some embodiments of any of the aspects, an iNA comprises a sequence that can specifically hybridize to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 15 nucleotides in length that can specifically hybridize to at least a portion of a target sequence described herein. In some embodiments of any of the aspects, an iNA comprises a sequence at least 20 nucleotides in length that can specifically hybridize to at least a portion of a target sequence described herein.

[0185] Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). The inhibitory nucleic acids described herein can include an RNA strand (the antisense strand) having a region which is 30 nucleotides or less in length, i.e., 15-30 nucleotides in length, generally 19-24 nucleotides in length, which region is substantially complementary to at least part the targeted mRNA transcript. The use of these iRNAs enables the targeted degradation of mRNA transcripts, resulting in decreased expression and / or activity of the target.

[0186] As used herein, the term “iRNA” refers to an agent that contains RNA (or modified nucleic acids as described below herein) and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. In some embodiments of any of the aspects, an iRNA as described herein effects inhibition of the expression and / or activity of a target, e.g., CXCR1 and / or CXCR2. In some embodiments of any of the aspects, contacting a cell with the inhibitor (e.g., an iRNA) results in a decrease in the target mRNA level in a cell by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, up to and including 100% of the target mRNA level found in the cell without the presence of the iRNA. In some embodiments of any of the aspects, administering an inhibitor (e.g., an iRNA) to a subject results in a decrease in the target mRNA level in the subject by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, up to and including 100% of the target mRNA level found in the subject without the presence of the iRNA.

[0187] In some embodiments of any of the aspects, the iRNA can be a dsRNA. A dsRNA includes two RNA strands that are sufficiently complementary to hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence. The target sequence can be derived from the sequence of an mRNA formed during the expression of the target, e.g., it can span one or more intron boundaries. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. Generally, the duplex structure is between 15 and 30 base pairs in length inclusive, more generally between 18 and 25 base pairs in length inclusive, yet more generally between 19 and 24 base pairs in length inclusive, and most generally between 19 and 21 base pairs in length, inclusive. Similarly, the region ofcomplementarity to the target sequence is between 15 and 30 base pairs in length inclusive, more generally between 18 and 25 base pairs in length inclusive, yet more generally between 19 and 24 base pairs in length inclusive, and most generally between 19 and 21 base pairs in length nucleotides in length, inclusive. In some embodiments of any of the aspects, the dsRNA is between 15 and 20 nucleotides in length, inclusive, and in other embodiments, the dsRNA is between 25 and 30 nucleotides in length, inclusive. As the ordinarily skilled person will recognize, the targeted region of an RNA targeted for cleavage will most often be part of a larger RNA molecule, often an mRNA molecule. Where relevant, a “part” of an mRNA target is a contiguous sequence of an mRNA target of sufficient length to be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway). dsRNAs having duplexes as short as 9 base pairs can, under some circumstances, mediate RNAi- directed RNA cleavage. Most often a target will be at least 15 nucleotides in length, preferably 15-30 nucleotides in length.

[0188] Exemplary embodiments of types of inhibitory nucleic acids can include, e.g., siRNA, shRNA, miRNA, and / or amiRNA, which are well known in the art. One skilled in the art would be able to design further siRNA, shRNA, or miRNA to target the nucleic acid sequence of CXCR1 (e.g., SEQ ID NO: 2) or CXCR2 (e.g., SEQ ID NOs 5-6), e.g., using publicly available design tools. siRNA, shRNA, or miRNA is commonly made using companies such as Dharmacon (Lafayette, CO) or Sigma Aldrich (St. Louis, MO).

[0189] In some embodiments of the various aspects described herein, the inhibitory nucleic acid is a guide nucleic acid (gNA). As used herein, the terms “guide nucleic acid,” “guide sequence,” “crRNA,” “guide RNA,” “single guide RNA,” “gRNA” or “CRISPR guide sequence” refer to a nucleic acid comprising a sequence that determines the specificity of an enzyme, e.g., the Cas DNA binding protein of a CRISPR / Cas system, to a polynucleotide target. The gNA can comprise a polynucleotide sequence with at least partial complementarity with a target nucleic acid sequence, sufficient to hybridize with the target nucleic acid sequence and to direct sequence-specific binding of an enzyme, e.g., a nuclease, to the target nucleic acid sequence.

[0190] In some embodiments, the enzyme directed by the gNA is a gene-editing protein, e.g., any nuclease that induces a nick or double-strand break into a desired recognition site. Such enzymes can be native or engineered. These breaks can then be repaired by the cell in one of two ways: non- homologous end joining and homology-directed repair (homologous recombination). In non-homologous end joining (NHEJ), the double-strand breaks are repaired by direct ligation of the break ends to one another. As such, no new nucleic acid material isinserted into the site, although some nucleic acid material may be lost, resulting in a deletion. In homology-directed repair, a donor polynucleotide with homology to the cleaved target DNA sequence can be used as a template for repair of the cleaved target DNA sequence, resulting in the transfer of genetic information from the donor polynucleotide to the target DNA. Therefore, new nucleic acid material may be inserted / copied into the site. The modifications of the target DNA due to NHEJ and / or homology-directed repair can be used for gene correction, gene replacement, gene tagging, transgene insertion, nucleotide deletion, gene disruption, gene mutation, etc.

[0191] In one embodiment, the gene-editing protein is a CRISPR-associated nuclease. The native prokaryotic CRISPR-associated nuclease system comprises an array of short repeats with intervening variable sequences of constant length (i.e., clusters of regularly interspaced short palindromic repeats), and CRISPR-associated ("Cas") nuclease proteins. The RNA of the transcribed CRISPR array is processed by a subset of the Cas proteins into small guide RNAs, which generally have two components as discussed below. There are at least three different systems: Type I, Type II and Type III. The enzymes involved in the processing of the RNA into mature crRNA are different in the 3 systems. In the native prokaryotic system, the guide RNA ("gRNA") comprises two short, non-coding RNA species referred to as CRISPR RNA ("crRNA") and trans-acting RNA ("tracrRNA"). In an exemplary system, the gRNA forms a complex with a nuclease, for example, a Cas nuclease. The gRNA: nuclease complex binds a target polynucleotide sequence having a protospacer adjacent motif ("PAM") and a protospacer, which is a sequence complementary to a portion of the gRNA. The recognition and binding of the target polynucleotide by the gRNA: nuclease complex induces cleavage of the target.

[0192] Any CRISPR-associated nuclease can be used in the system and methods of the invention. CRISPR nuclease systems are known to those of skill in the art, e.g., Cas9, Casl2, Casl2a, or the like, see Patents / applications 8,993,233, US 2015 / 0291965, US 2016 / 0175462, US 2015 / 0020223, US 2014 / 0179770, 8,697,359; 8,771,945; 8, 795,965; WO 2015 / 191693; US 8,889,418; WO 2015 / 089351; WO 2015 / 089486; WO 2016 / 028682; WO 2016 / 049258; WO 2016 / 094867; WO 2016 / 094872; WO 2016 / 094874; WO 2016 / 112242; US 2016 / 0153004; US 2015 / 0056705; US 2016 / 0090607; US 2016 / 0029604; 8,865,406; 8,871,445; each of which are incorporated by reference in their entirety. The nuclease can also be a phage Cas nuclease, e.g., CasO (e.g., Pausch et al. Science 369:333-7 (2020); which is incorporated by reference herein in its entirety).

[0193] The full-length guide nucleic acid strand can be any length. For example, the guide nucleic acid strand can be about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments of the various aspects described herein, a nucleic acid strand is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. For example, the guide nucleic acid sequence is 10-30 nucleotides long.

[0194] In addition to a sequence that is complementary to a target nucleic acid, in some embodiments, the gNA also comprises a scaffold sequence. Expression of a gNA encoding both a sequence complementary to a target nucleic acid and scaffold sequence has the dual function of both binding (hybridizing) to the target nucleic acid and recruiting the endonuclease to the target nucleic acid, which may result in site-specific CRISPR activity. In some embodiments, such a chimeric gNA may be referred to as a single guide RNA (sgRNA).

[0195] In some embodiments of the various aspects described herein, the guide nucleic acid is designed using a guide design tool (e.g., Benchling™; Broad Institute GPP™; CasOFFinder™; CHOPCHOP™; CRISPOR™; Deskgen™; E-CRISP™; Geneious™; GenHub™; GUIDES™ (e.g., for library design); Horizon Discovery™; IDT™; Off-Spotter™; and Synthego™; which are available on the world wide web).

[0196] In some embodiments of any of the aspects, the RNA of an iRNA, e.g., a dsRNA, is chemically modified to enhance stability or other beneficial characteristics. The nucleic acids described herein may be synthesized and / or modified by methods well established in the art, such as those described in “Current protocols in nucleic acid chemistry,” Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated herein by reference. Modifications include, for example, (a) end modifications, e.g., 5’ end modifications (phosphorylation, conjugation, inverted linkages, etc.) 3’ end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), (b) base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases, (c) sugar modifications (e.g., at the 2’ position or 4’ position) or replacement of the sugar, as well as (d) backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of RNA compounds useful in the embodiments described herein include, but are not limited to RNAs containing modified backbones or no natural intemucleoside linkages. RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified RNAs that do not have aphosphorus atom in their intemucleoside backbone can also be considered to be oligonucleosides. In some embodiments of any of the aspects, the modified RNA will have a phosphorus atom in its internucleoside backbone.

[0197] Modified RNA backbones can include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3 '-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3 '-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those) having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts and free acid forms are also included. Modified RNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; others having mixed N, O, S and CH2 component parts, and oligonucleosides with heteroatom backbones, and in particular — CH2— NH— CH2— , —CH2—N(CH3)—O—CH2— [known as a methylene (methylimino) or MMI backbone], -CH2-O-N(CH3)-CH2-, -CH2-N(CH3)-N(CH3)-CH2- and -N(CH3)- CH2—CH2— [wherein the native phosphodiester backbone is represented as — O— P— O— CH2— ]•

[0198] In other RNA mimetics suitable or contemplated for use in iRNAs, both the sugar and the intemucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone.

[0199] The RNA of an iRNA can also be modified to include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2' and 4' carbons. This structure effectively "locks" the ribose in the 3'-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(l):439-447; Mook, OR. et al., (2007) Mol Cane Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193).

[0200] Modified RNAs can also contain one or more substituted sugar moieties. The iRNAs, e.g., dsRNAs, described herein can include one of the following at the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted Cl to CIO alkyl or C2 to CIO alkenyl and alkynyl. Exemplary suitable modifications include O[(CH2)nO] mCH3, O(CH2).nOCH3, O(CH2)nNH2, O(CH2) nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. In some embodiments of any of the aspects, dsRNAs include one of the following at the 2' position: Cl to CIO lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an iRNA, or a group for improving the pharmacodynamic properties of an iRNA, and other substituents having similar properties. In some embodiments of any of the aspects, the modification includes a 2' methoxyethoxy (2'-O— CH2CH2OCH3, also known as 2'-O-(2- methoxyethyl) or 2'-M0E) (Martin et al., Helv. Chim. Acta, 1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2'-dimethylaminooxyethoxy, i.e., a O(CH2)2ON(CH3)2 group, also known as 2'-DMA0E, as described in examples herein below, and 2'-dimethylaminoethoxyethoxy (also known in the art as 2'-O- dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-O— CH2— O— CH2— N(CH2)2, also described in examples herein below.

[0201] Other modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2'- OCH2CH2CH2NH2) and 2'-fluoro (2'-F). Similar modifications can also be made at other positions on the RNA of an iRNA, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked dsRNAs and the 5' position of 5' terminal nucleotide. iRNAs may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar.

[0202] An inhibitory nucleic acid can also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5 -methylcytosine (5-me-C), 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8- thioalkyl, 8-hydroxyl anal other 8-substituted adenines and guanines, 5-halo, particularly 5- bromo, 5 -trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3- deazaguanine and 3 -deazaadenine. Certain of these nucleobases are particularly useful for increasing the binding affinity of the inhibitory nucleic acids featured in the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5- methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications.

[0203] The preparation of the modified nucleic acids, backbones, and nucleobases described above are well known in the art.

[0204] Another modification of an inhibitory nucleic acid featured in the invention involves chemically linking to the inhibitory nucleic acid to one or more ligands, moieties or conjugates that enhance the activity, cellular distribution, pharmacokinetic properties, or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4: 1053-1060), a thioether, e.g., beryl -S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10: 1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), a phospholipid, e.g., di-hexadecyl -rac-glycerol or triethyl-ammonium l,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecyl amine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937).

[0205] Antibody inhibitors of IL-8 Receptors

[0206] Antibodies that specifically bind IL-8 receptors (i.e., CXCR1 and CXCR2) can be used for inhibition in vivo, in vitro, or ex vivo. The IL-8 receptor inhibitory activity of a given antibody, or, for that matter, any IL-8 receptor inhibitor, can be assessed using methods known in the art or described herein. Specific binding is typically defined as binding that does not recognize other antigens, such as a protein, nucleotide, chemical residue, etc., at a detectable level in an assay used. Accordingly, in some embodiments of any one of the aspects described herein, the inhibitor of the IL-8 receptor (i.e., CXCR1 or CXCR2) is an antibody or an antigen binding fragment thereof. Generally, the antibody or the antigen binding fragment thereof binds an epitope on the IL-8 receptor such that the binding inhibits a function and / or activity of the IL-8 receptor.

[0207] Antibodies that can be used according to the methods described herein, include complete immunoglobulins, antigen binding fragments of immunoglobulins, as well as antigen binding proteins that comprise antigen binding domains of immunoglobulins. Antigen binding fragments of immunoglobulins include, for example, Fab, Fab’, F(ab’)2, scFv and dAbs. Modified antibody formats have been developed which retain binding specificity, but have other characteristics that may be desirable, including for example, bi specificity, multivalence (more than two binding sites), and compact size (e.g., binding domains alone). Single chain antibodies lack some or all of the constant domains of the whole antibodies from which they are derived. Therefore, they can overcome some of the problems associated with the use of whole antibodies. For example, single-chain antibodies tend to be free of certain undesired interactions between heavy-chain constant regions and other biological molecules. Additionally, single-chain antibodies are considerably smaller than whole antibodies and can have greater permeability than whole antibodies, allowing single-chain antibodies to localize and bind to target antigen-binding sites more efficiently. Furthermore, the relatively small size of single-chain antibodies makes them less likely to provoke an unwanted immune response in a recipient than whole antibodies.

[0208] Multiple single chain antibodies, each single chain having one VH and one VL domain covalently linked by a first peptide linker, can be covalently linked by at least one or more peptide linker to form multivalent single chain antibodies, which can be monospecific or multispecific. Each chain of a multivalent single chain antibody includes a variable light chain fragment and a variable heavy chain fragment, and is linked by a peptide linker to at least one other chain. The peptide linker is composed of at least fifteen amino acid residues. The maximum number of linker amino acid residues is approximately one hundred.

[0209] Two single chain antibodies can be combined to form a diabody, also known as a bivalent dimer. Diabodies have two chains and two binding sites, and can be monospecific or bispecific. Each chain of the diabody includes a VH domain connected to a VL domain. The domains are connected with linkers that are short enough to prevent pairing between domains on the same chain, thus driving the pairing between complementary domains on different chains to recreate the two antigen-binding sites.

[0210] Three single chain antibodies can be combined to form triabodies, also known as trivalent trimers. Triabodies are constructed with the amino acid terminus of a VL or VH domain directly fused to the carboxyl terminus of a VL or VH domain, i.e., without any linker sequence. The triabody has three Fv heads with the polypeptides arranged in a cyclic, head-to- tail fashion. A possible conformation of the triabody is planar with the three binding sites located in a plane at an angle of 120 degrees from one another. Triabodies can be monospecific, bispecific or trispecific.

[0211] Thus, antibodies useful in the methods described herein include, but are not limited to, naturally occurring antibodies, bivalent fragments such as (Fab')2, monovalent fragments such as Fab, single chain antibodies, single chain Fv (scFv), single domain antibodies, multivalent single chain antibodies, diabodies, triabodies, and the like that bind specifically with an antigen.

[0212] Antibodies can also be raised against a nucleotide, polypeptide or portion of a polypeptide by methods known to those skilled in the art. Antibodies are readily raised in animals such as rabbits or mice by immunization with the gene product, or a fragment thereof. Immunized mice are particularly useful for providing sources of B cells for the manufacture of hybridomas, which in turn are cultured to produce large quantities of monoclonal antibodies. Antibody manufacture methods are described in detail, for example, in Harlow et al., 1988. While both polyclonal and monoclonal antibodies can be used in the methods described herein, it is preferred that a monoclonal antibody is used where conditions require increased specificity for a particular protein.

[0213] The term “intrabodies” as used herein, refers to a method wherein to target intracellular endogenous proteins as described in US Patent 6004940. Briefly, the method comprises the intracellular expression of an antibody capable of binding to the target. A DNA sequence is delivered to a cell, the DNA sequence contains a sufficient number of nucleotides coding for the portion of an antibody capable of binding to the target operably linked to a promoter that will permit expression of the antibody in the cell(s) of interest. The antibody is then expressed intracellularly and binds to the target, thereby disrupting the target from its normal actions.

[0214] “Antigen-binding fragments” include, inter alia, Fab, Fab', F(ab')2, Fv, dAb, and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), single domain antibodies, chimeric antibodies, diabodies and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. The terms Fab, Fc, pFc', F(ab') 2 and Fv are employed with standard immunological meanings [Klein, Immunology (John Wiley, New York, N.Y., 1982); Clark, W. R. (1986) The Experimental Foundations of Modern Immunology (Wiley & Sons, Inc., New York); Roitt, I. (1991) Essential Immunology, 7th Ed., (Blackwell Scientific Publications, Oxford)].

[0215] Antibody inhibitors of IL-8 receptors (i.e., CXCR1 and CXCR2) can include polyclonal and monoclonal antibodies and antigen-binding derivatives or fragments thereof.

[0216] In some embodiments of any one of the aspects described herein, the inhibitor is an anti-CXCRl antibody, anti-CXCR2 antibody, anti-IL-8 receptor antibody, or an antigen binding fragment thereof. Generally, the antibody or the antigen binding fragment thereof binds an epitope on the IL-8 receptor such that the binding inhibits a function and / or activity of the IL-8 receptor. In some embodiments of any one of the aspects described herein, the antibody binds to polypeptide of comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NOs: 5-6. Exemplary anti-CXCRl and anti-CXCR2 antibodies are commercially available and include, but are not limited to CXCR1 Monoclonal Antibody (501), (Cat. No. # MA1-2O6, Invitrogen, Carlsbad, CA); CXCR1 Monoclonal Antibody (42705.111), (Cat. No. # MAI-24668, Invitrogen, Carlsbad, CA); Mouse CXCR1 / IL-8RA Antibody (Cat. No. #MAB8628, Bio-Techne, Minneapolis, MN); CXCR2 Monoclonal Antibody (GT547) (Cat. No. #MA5-31520, Invitrogen, Carlsbad, CA); CXCR2 Monoclonal Antibody (48311.211) (Cat No. #MAl-24669, Invitrogen, Carlsbad, CA); Anti- CXCR2 monoclonal antibody 4N0 (Cat. No. #DCABH-11169, Creative Diagnostics, Shirley,NY); Anti-CXCR2 monoclonal antibody fCjp6F9-D8-G20 (Cat. No. #DCABH-11170, Creative Diagnostics, Shirley, NY).

[0217] Methods of obtaining antibodies against an antigen are well known in the art and available to one of skill in the art.

[0218] Small molecule inhibitors of IL-8 Receptors

[0219] In some embodiments of any one of the aspects described herein, the inhibitor of the IL-8 receptors (i.e., CXCR1 and CXCR2) is a small molecule. In one embodiment, the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933. In one embodiment, the small molecule inhibitor of IL-8 receptor is reparixin.

[0220] Any inhibitors of the IL-8 receptors can be used in the methods described herein. For example, in some embodiments, an IL-8 receptor inhibitor can be a small molecule inhibitor. Small molecule inhibitors of IL-8 receptors are known in the art (see, for example, Prajapati et al. 2023, Cancer Lett.; Sun et al. 2019. JCI Insight.; each of which is incorporated by reference herein in its entirety). In some embodiments, the IL-8 receptor inhibitor can be specific for an IL-8 receptor (i.e., CXCR1 and CXCR2). IL-8 receptor (i.e., CXCR1 and CXCR2) inhibitors are commercially available, e.g., SCH-479833, SX-682, SCH-527123, hydroxypropyl-P- cyclodextrin (20%), reparixin, navarixin, SB656933, AZD5069, and GSK1325756.

[0221] Generally, the small molecule inhibitor binds with an IL-8 receptor (i.e, CXCR1, CXCR2) and inhibits a function and / or activity of an IL-8 receptor. As used herein, the term “small molecules” refers to natural or synthetic molecules including, but not limited to, amino acids, peptides, peptidomimetics, polynucleotides, aptamers, nucleotide analogs, organic or inorganic compounds (i.e., including heterorganic and organometallic compounds), saccharides (e.g., mono, di, tri and polysaccharides), steroids, hormones, pharmaceutically derived drugs (e.g., synthetic or naturally occurring), lipids, derivatives of these (e.g., esters and salts of these), fragments of these, and conjugates of these. In some implementations the small molecules have a molecular weight less than about 5,000 Da, organic or inorganic compounds having a molecular weight less than about 2,500 Da, organic or inorganic compounds having a molecular weight less than about 1,000 Da, organic or inorganic compounds having a molecular weight less than about 500 Da. In some implementations the small molecule has a molecular weight of less than about 1000 Da.

[0222] In some embodiments of any one of the aspects described herein, the small molecule inhibitor inhibits an IL-8 receptor (i.e., CXCR1, CXCR2). In some preferred embodiments,the small molecule can contact an IL-8 receptor (i.e., CXCR1, CXCR2) in a covalent or non- covalent manner.

[0223] In some embodiments of any one of the aspects described herein, the small molecule inhibitor is selected from the group consisting of SCH-479833, SX-682, SCH-527123, hydroxypropyl-P-cyclodextrin (20%), reparixin, navarixin, SB656933, AZD5069, and GSK1325756. In a preferred embodiment, the small molecule inhibitor is reparixin.

[0224] Reparixin is a noncompetitive allosteric inhibitor of CXCR1 and CXCR2, cognate receptors of IL8 (CXCL8), able to (Bertini, R., et al. Proc Nat Acad Sci USA 2004, 101 : 11791) block a range of activities related to IL8 signaling, including leukocyte recruitment and other inflammatory responses, without affecting the binding between the ligand and the receptor (Bertini, R., et al. Proc Nat Acad Sci USA 2004, 101 : 11791). Reparixin can also be known as repertaxin and can be used interchangeably throughout the application. Reparixin is the INN name of R(-)-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide (previously known as DF 1681Y) and it was first disclosed in International application W00024710, incorporated by reference herein in its entirety.. However, preventative and therapeutic effects of reparixin to reduce inflammation, pain, and / or at least one lesion of, for example but not limited to, female reproductive organs have not been suggested or explored.

[0225] In various embodiments, compounds of small molecule inhibitors of IL-8 receptors (i.e., reparixin) include enantiomers, derivatives, prodrugs, and pharmaceutically acceptable salts thereof. The term “derivative” as used herein means any chemical, conservative substitution, or structural modification of an agent. The chemical substance can relate structurally to another, i.e., an “original” substance, which can be referred to as a “parent” compound. The derivative can improve characteristics of the agent or small molecule such as pharmacodynamics, pharmacokinetics, absorption, distribution, delivery, targeting to a specific receptor, or efficacy. A “derivative” can be made from the structurally-related parent compound in one or more steps. The general physical and chemical properties of a derivative are also similar to the parent compound.

[0226] One aspect provided herein is a composition comprising any of the agents that inhibits an IL-8 receptor as described herein. In one embodiment, the composition comprises at least two agents described herein.

[0227] In one embodiment, the agent that inhibits IL-8 receptor is a small molecule inhibitor of IL-8 receptor. Exemplary small molecule inhibitors of IL-8 include AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933.

[0228] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0229] In one embodiment, the composition further comprises a second therapeutic agent. Exemplary second therapeutic agent include, for example, a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of a lesion(s).Second Therapeutic Agent / Combination Therapies

[0230] In various embodiment, the methods described herein further comprise administering a second agent and / or treatment to the subject, e.g., as part of a combinatorial therapy. The additional therapy can be administered prior to, simultaneously with, or after administering the IL-8 receptor inhibitor. In some embodiments, the method further comprises administering to a subject in need thereof a second therapeutic agent.

[0231] The phrase “combination therapy” or “a second therapeutic agent” as used herein means the administration of an IL-8 receptor inhibitor and one or more additional therapies as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period. The time period may be in minutes, hours, days or weeks depending upon the combination selected.

[0232] Combination therapy includes administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be done, for example, by administering to the subject a single pill having a fixed ratio of each therapeutic agent or in multiple, single pills for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered may or may not be important.

[0233] Combination therapy also can mean the administration of one or more inhibitors of an IL-8 receptor in further combination with other compounds and non-drug therapies, such as, but not limited to, a non-steroidal anti-inflammatory drug (NS AID), an analgesic, a hormonal agent, and surgical removal of the at least one lesion. An analgesic is a drug or group of drugs used to achieve relief from pain. Hormonal therapy, as used herein involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Examples of NSAIDs include but are not limited to ketorolac, diclofenac, naproxen, meloxicam, diclofenac, esomeprazole, ibuprofen, nabumetone, and indomethancin. One who is skilled in the art will be able to select an appropriate NSAID and administer an effective dosage of an NSAID in combination with an IL-8 receptor inhibitor to a subject in need thereof. Examples of an analgesic include, but are not limited to an NSAID, a COX-2 inhibitor, an opioid, nefopam, flupirtin, and ziconotide. One who is skilled in the art will be able to select an appropriate analgesic and administer an effective dosage of an analgesic in combination with an IL-8 receptor inhibitor to a subject in need thereof. Examples of a hormonal agent include, but are not limited to, tamoxifen, aromatase inhibitors, GnRH analogues, selective estrogen receptor modulators, antiandrogens, progestogens, androgens, estrogens, and somatostatin analogs.Methods for Determining Expression Levels

[0234] In some embodiments of any of the aspects, the methods described herein are directed to determination of the expression level of IL-8 receptor (e.g., CXCR1, CXCR2) in a biological sample of a subject.

[0235] In some embodiments of any of the aspects, the methods described herein are directed to determination of the expression level of a gene product (e.g., protein and / or gene transcript such as mRNA) in a biological sample from a subject.

[0236] In one embodiment of any aspect, IL-8 receptor expression and / or activity is inhibited by at least 1 %, at least 2 %, at least 3 %, at least 4 %, at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 21 %, at least 22 %, at least 23 %, at least 24 %, at least 25 %, at least 26 %, at least 27 %, at least 28 %, at least 29 %, at least 30 %, at least 31 %, at least 32 %, at least 33 %, at least 34 %, at least 35 %, at least 36 %, at least 37 %, at least 38 %, at least 39 %, at least 40 %, at least 41 %, at least 42 %, at least 43 %, at least 44 %, at least 45 %, at least 46 %, at least 47 %, at least48 %, at least 49 %, at least 50 %, at least 51 %, at least 52 %, at least 53 %, at least 54 %, at least 55 %, at least 56 %, at least 57 %, at least 58 %, at least 59 %, at least 60 %, at least 61 %, at least 62 %, at least 63 %, at least 64 %, at least 65 %, at least 66 %, at least 67 %, at least 68 %, at least 69 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least 95 %, at least 96 %, at least 97 %, at least 98 %, at least 99 %,or more as compared to expression and / or activity prior to administration, or a reasonable control. As used herein, “reasonable control” refers to an otherwise identical sample that is not administered an IL-8 receptor inhibitor.

[0237] In some embodiments of any of the aspects, measurement is the level of a target and / or detection of the level or presence of a target, e.g., of an expression product (nucleic acid or polypeptide of one of the genes described herein) or a mutation can comprise a transformation. As used herein, the term “transforming” or “transformation” refers to changing an object or a substance, e.g., biological sample, nucleic acid or protein, into another substance. The transformation can be physical, biological or chemical. Exemplary physical transformation includes, but is not limited to, pre-treatment of a biological sample, e.g., cardiomyocytes or heart tissue from a patient diagnosed with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. A biological / chemical transformation can involve the action of at least one enzyme and / or a chemical reagent in a reaction. For example, a DNA sample can be digested into fragments by one or more restriction enzymes, or an exogenous molecule can be attached to a fragmented DNA sample with a ligase. In some embodiments of any of the aspects, a DNA sample can undergo enzymatic replication, e.g., by polymerase chain reaction (PCR).

[0238] Transformation, measurement, and / or detection of a target molecule, e.g., a mRNA or polypeptide can comprise contacting a sample obtained from a subject with a reagent (e.g., a detection reagent) which is specific for the target, e.g., a target-specific reagent. In some embodiments of any of the aspects, the target-specific reagent is detectably labeled. In some embodiments of any of the aspects, the target-specific reagent is capable of generating a detectable signal. In some embodiments of any of the aspects, the target-specific reagent generates a detectable signal when the target molecule is present.

[0239] Methods to measure gene expression products are known to a skilled artisan. Such methods to measure gene expression products, e.g., protein level, include ELISA (enzymelinked immunosorbent assay), western blot, immunoprecipitation, and immunofluorescence using detection reagents such as an antibody or protein binding agents. Alternatively, a peptide can be detected in a subject by introducing into a subject a labeled anti-peptide antibody and other types of detection agent. For example, the antibody can be labeled with a detectable marker whose presence and location in the subject is detected by standard imaging techniques.

[0240] In some embodiments of any of the aspects, immunohistochemistry (“IHC”) and immunocytochemistry (“ICC”) techniques can be used. IHC is the application of immunochemistry to tissue sections, whereas ICC is the application of immunochemistry to cells or tissue imprints after they have undergone specific cytological preparations such as, for example, liquid-based preparations. Immunochemistry is a family of techniques based on the use of an antibody, wherein the antibodies are used to specifically target molecules inside or on the surface of cells. The antibody typically contains a marker that will undergo a biochemical reaction, and thereby experience a change of color, upon encountering the targeted molecules. In some instances, signal amplification can be integrated into the particular protocol, wherein a secondary antibody, that includes the marker stain or marker signal, follows the application of a primary specific antibody.

[0241] In some embodiments of any of the aspects, the assay can be a Western blot analysis. Alternatively, proteins can be separated by two-dimensional gel electrophoresis systems. Two- dimensional gel electrophoresis is well known in the art and typically involves iso-electric focusing along a first dimension followed by SDS-PAGE electrophoresis along a second dimension. These methods also require a considerable amount of cellular material. The analysis of 2D SDS-PAGE gels can be performed by determining the intensity of protein spots on the gel, or can be performed using immune detection. In other embodiments, protein samples are analyzed by mass spectroscopy.

[0242] Immunological tests can be used with the methods and assays described herein and include, for example, competitive and non-competitive assay systems using techniques such as Western blots, radioimmunoassay (RIA), ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, immunodiffusion assays, agglutination assays, e.g., latex agglutination, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, e.g., FIA (fluorescence-linked immunoassay), chemiluminescence immunoassays (CLIA), electrochemiluminescence immunoassay (ECLIA, counting immunoassay (CIA), lateral flow tests or immunoassay (LFIA), magnetic immunoassay (MIA), and protein A immunoassays. Methods for performing such assays are known in the art, provided an appropriate antibody reagent is available. In someembodiments of any of the aspects, the immunoassay can be a quantitative or a semi- quantitative immunoassay.

[0243] An immunoassay is a biochemical test that measures the concentration of a substance in a biological sample, typically a fluid sample such as blood or serum, using the interaction of an antibody or antibodies to its antigen. The assay takes advantage of the highly specific binding of an antibody with its antigen. For the methods and assays described herein, specific binding of the target polypeptides with respective proteins or protein fragments, or an isolated peptide, or a fusion protein described herein occurs in the immunoassay to form a target protein / peptide complex. The complex is then detected by a variety of methods known in the art. An immunoassay also often involves the use of a detection antibody.

[0244] Enzyme-linked immunosorbent assay, also called ELISA, enzyme immunoassay or EIA, is a biochemical technique used mainly in immunology to detect the presence of an antibody or an antigen in a sample. The ELISA has been used as a diagnostic tool in medicine and plant pathology, as well as a quality control check in various industries.

[0245] In one embodiment, an ELISA involving at least one antibody with specificity for the particular desired antigen (e.g., any of the targets as described herein) can also be performed. A known amount of sample and / or antigen is immobilized on a solid support (usually a polystyrene micro titer plate). Immobilization can be either non-specific (e.g., by adsorption to the surface) or specific (e.g., where another antibody immobilized on the surface is used to capture antigen or a primary antibody). After the antigen is immobilized, the detection antibody is added, forming a complex with the antigen. The detection antibody can be covalently linked to an enzyme, or can itself be detected by a secondary antibody which is linked to an enzyme through bio-conjugation. Between each step the plate is typically washed with a mild detergent solution to remove any proteins or antibodies that are not specifically bound. After the final wash step the plate is developed by adding an enzymatic substrate to produce a visible signal, which indicates the quantity of antigen in the sample. Older ELISAs utilize chromogenic substrates, though newer assays employ fluorogenic substrates with much higher sensitivity.

[0246] In another embodiment, a competitive ELISA is used. Purified antibodies that are directed against a target polypeptide or fragment thereof are coated on the solid phase of multiwell plate, i.e., conjugated to a solid surface. A second batch of purified antibodies that are not conjugated on any solid support is also needed. These non-conjugated purified antibodies are labeled for detection purposes, for example, labeled with horseradish peroxidase to produce a detectable signal. A sample (e.g., a blood sample) from a subj ect is mixed with a known amountof desired antigen (e.g., a known volume or concentration of a sample comprising a target polypeptide) together with the horseradish peroxidase labeled antibodies and the mixture is then added to coated wells to form competitive combination. After incubation, if the polypeptide level is high in the sample, a complex of labeled antibody reagent-antigen will form. This complex is free in solution and can be washed away. Washing the wells will remove the complex. Then the wells are incubated with TMB (3, 3', 5, 5'-tetramethylbenzidene) color development substrate for localization of horseradish peroxidase-conjugated antibodies in the wells. There will be no color change or little color change if the target polypeptide level is high in the sample. If there is little or no target polypeptide present in the sample, a different complex in formed, the complex of solid support bound antibody reagents-target polypeptide. This complex is immobilized on the plate and is not washed away in the wash step. Subsequent incubation with TMB will produce significant color change. Such a competitive ELSA test is specific, sensitive, reproducible and easy to operate.

[0247] There are other different forms of ELISA, which are well known to those skilled in the art. The standard techniques known in the art for ELISA are described in “Methods in Immunodiagnosis”, 2nd Edition, Rose and Bigazzi, eds. John Wiley & Sons, 1980; Alhajj M, Zubair M, Farhana A. Enzyme Linked Immunosorbent Assay. [Updated 2023 Apr 23], In: StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https: / / ncbi.nlm.nih.gov / books / NBK555922 / and Oellerich, M. 1984, J. Clin. Chem. Clin. Biochem. 22:895-904. These references are hereby incorporated by reference in their entirety.

[0248] In one embodiment, the levels of a polypeptide in a sample can be detected by a lateral flow immunoassay test (LFIA), also known as the immunochromatographic assay, or strip test. LFIAs are a simple device intended to detect the presence (or absence) of antigen, e.g., a polypeptide, in a fluid sample. There are currently many LFIA tests used for medical diagnostics, either for home testing, point of care testing, or laboratory use. LFIA tests are a form of immunoassay in which the test sample flows along a solid substrate via capillary action. After the sample is applied to the test strip it encounters a colored reagent (generally comprising antibody specific for the test target antigen) bound to microparticles which mixes with the sample and transits the substrate encountering lines or zones which have been pretreated with another antibody or antigen. Depending upon the level of target polypeptides present in the sample the colored reagent can be captured and become bound at the test line or zone. LFIAs are essentially immunoassays adapted to operate along a single axis to suit the test strip format or a dipstick format. Strip tests are extremely versatile and can be easily modified by one skilled in the art for detecting an enormous range of antigens from fluid samples such as urine, blood,water, and / or homogenized tissue samples etc. Strip tests are also known as dip stick tests, the name bearing from the literal action of “dipping” the test strip into a fluid sample to be tested. LFIA strip tests are easy to use, require minimum training and can easily be included as components of point-of-care test (POCT) diagnostics to be use on site in the field. LFIA tests can be operated as either competitive or sandwich assays. Sandwich LFIAs are similar to sandwich ELISA. The sample first encounters colored particles which are labeled with antibodies raised to the target antigen. The test line will also contain antibodies to the same target, although it may bind to a different epitope on the antigen. The test line will show as a colored band in positive samples. In some embodiments of any of the aspects, the lateral flow immunoassay can be a double antibody sandwich assay, a competitive assay, a quantitative assay or variations thereof. Competitive LFIAs are similar to competitive ELISA. The sample first encounters colored particles which are labeled with the target antigen or an analogue. The test line contains antibodies to the target / its analogue. Unlabelled antigen in the sample will block the binding sites on the antibodies preventing uptake of the colored particles. The test line will show as a colored band in negative samples. There are a number of variations on lateral flow technology. It is also possible to apply multiple capture zones to create a multiplex test.

[0249] The use of “dip sticks” or LFIA test strips and other solid supports have been described in the art in the context of an immunoassay for a number of antigen biomarkers. U.S. Pat. Nos. 4,943,522; 6,485,982; 6,187,598; 5,770,460; 5,622,871; 6,565,808, U. S. patent applications Ser. No. 10 / 278,676; U.S. Ser. No. 09 / 579,673 and U.S. Ser. No. 10 / 717,082, which are incorporated herein by reference in their entirety, are non-limiting examples of such lateral flow test devices. Examples of patents that describe the use of “dip stick” technology to detect soluble antigens via immunochemical assays include, but are not limited to US Patent Nos. 4,444,880; 4,305,924; and 4,135,884; which are incorporated by reference herein in their entireties. The apparatuses and methods of these three patents broadly describe a first component fixed to a solid surface on a “dip stick” which is exposed to a solution containing a soluble antigen that binds to the component fixed upon the “dip stick,” prior to detection of the component-antigen complex upon the stick. It is within the skill of one in the art to modify the teachings of this “dip stick” technology for the detection of polypeptides using antibody reagents as described herein.

[0250] Other techniques can be used to detect the level of a polypeptide in a sample. One such technique is the dot blot, an adaptation of Western blotting (Towbin et at., Proc. Nat. Acad. Sci. 76:4350 (1979)). In a Western blot, the polypeptide or fragment thereof can be dissociatedwith detergents and heat, and separated on an SDS-PAGE gel before being transferred to a solid support, such as a nitrocellulose or PVDF membrane. The membrane is incubated with an antibody reagent specific for the target polypeptide or a fragment thereof. The membrane is then washed to remove unbound proteins and proteins with non-specific binding. Detectably labeled enzyme-linked secondary or detection antibodies can then be used to detect and assess the amount of polypeptide in the sample tested. A dot blot immobilizes a protein sample on a defined region of a support, which is then probed with antibody and labelled secondary antibody as in Western blotting. The intensity of the signal from the detectable label in either format corresponds to the amount of enzyme present, and therefore the amount of polypeptide. Levels can be quantified, for example by densitometry.

[0251] In some embodiments of any of the aspects, the level of a target can be measured, by way of non-limiting example, by Western blot; immunoprecipitation; enzyme-linked immunosorbent assay (ELISA); radioimmunological assay (RIA); sandwich assay; fluorescence in situ hybridization (FISH); immunohistological staining; radioimmunometric assay; immunofluoresence assay; mass spectroscopy and / or immunoelectrophoresis assay.

[0252] In certain embodiments, the expression levels as described herein can be determined by determining the level of messenger RNA (mRNA) expression of the genes described herein. Such molecules can be isolated, derived, or amplified from a biological sample, such as a blood sample. Techniques for the detection of mRNA expression is known by persons skilled in the art, and can include but not limited to, PCR procedures, RT-PCR, quantitative RT-PCR Northern blot analysis, differential gene expression, RNAse protection assay, microarray -based analysis, next-generation sequencing; hybridization methods, etc.

[0253] In general, the PCR procedure describes a method of gene amplification which is comprised of (i) sequence-specific hybridization of primers to specific genes or sequences within a nucleic acid sample or library, (ii) subsequent amplification involving multiple rounds of annealing, elongation, and denaturation using a thermostable DNA polymerase, and (iii) screening the PCR products for a band of the correct size or sequence. The primers used are oligonucleotides of sufficient length and appropriate sequence to provide initiation of polymerization, i.e., each primer is specifically designed to be complementary to a strand of the genomic locus to be amplified. In an alternative embodiment, mRNA level of gene expression products described herein can be determined by reverse-transcription (RT) PCR and by quantitative RT-PCR (QRT-PCR) or real-time PCR methods. Methods of RT-PCR and QRT-PCR are well known in the art.

[0254] In some embodiments of any of the aspects, the level of an mRNA can be measured by a quantitative sequencing technology, e.g., a quantitative next-generation sequence technology. Methods of sequencing a nucleic acid sequence are well known in the art. Briefly, a sample obtained from a subject can be contacted with one or more primers which specifically hybridize to a single-strand nucleic acid sequence flanking the target gene sequence and a complementary strand is synthesized. In some next-generation technologies, an adaptor (double or single-stranded) is ligated to nucleic acid molecules in the sample and synthesis proceeds from the adaptor or adaptor compatible primers. In some third-generation technologies, the sequence can be determined, e.g., by determining the location and pattern of the hybridization of probes, or measuring one or more characteristics of a single molecule as it passes through a sensor (e.g., the modulation of an electrical field as a nucleic acid molecule passes through a nanopore). Exemplary methods of sequencing include, but are not limited to, Sanger sequencing, dideoxy chain termination, high-throughput sequencing, next generation sequencing, 454 sequencing, SOLiD sequencing, polony sequencing, Illumina sequencing, Ion Torrent sequencing, sequencing by hybridization, nanopore sequencing, Helioscope sequencing, single molecule real time sequencing, RNAP sequencing, and the like. Methods and protocols for performing these sequencing methods are known in the art, see, e.g., “Next Generation Genome Sequencing” Ed. Michal Janitz, Wiley-VCH; “High-Throughput Next Generation Sequencing” Eds. Kwon and Rieke, Humanna Press, 2011; Slatko BE, Gardner AF, Ausubel FM. Overview of Next-Generation Sequencing Technologies. Curr Protoc Mol Biol. 2018 Apr;122(l):e59. doi: 10.1002 / cpmb.59. PMID: 29851291; PMCID: PMC6020069, and Sambrook et al., Molecular Cloning: A Laboratory Manual (4 ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., USA (2012); which are incorporated by reference herein in their entireties.

[0255] Nucleic acid and ribonucleic acid (RNA) molecules can be isolated from a particular biological sample using any of a number of procedures, which are well-known in the art, the particular isolation procedure chosen being appropriate for the particular biological sample. For example, freeze-thaw and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from solid materials; heat and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from urine; and proteinase K extraction can be used to obtain nucleic acid from blood (Roiff, A et al. PCR: Clinical Diagnostics and Research, Springer (1994)).

[0256] In some embodiments of any of the aspects, one or more of the reagents (e.g., an antibody reagent and / or nucleic acid probe) described herein can comprise a detectable label and / or comprise the ability to generate a detectable signal (e.g., by catalyzing reactionconverting a compound to a detectable product). Detectable labels can comprise, for example, a light-absorbing dye, a fluorescent dye, or a radioactive label. Detectable labels, methods of detecting them, and methods of incorporating them into reagents (e.g., antibodies and nucleic acid probes) are well known in the art.

[0257] In some embodiments of any of the aspects, detectable labels can include labels that can be detected by spectroscopic, photochemical, biochemical, immunochemical, electromagnetic, radiochemical, or chemical means, such as fluorescence, chemifluoresence, or chemiluminescence, or any other appropriate means. The detectable labels used in the methods described herein can be primary labels (where the label comprises a moiety that is directly detectable or that produces a directly detectable moiety) or secondary labels (where the detectable label binds to another moiety to produce a detectable signal, e.g., as is common in immunological labeling using secondary and tertiary antibodies). The detectable label can be linked by covalent or non-covalent means to the reagent. Alternatively, a detectable label can be linked such as by directly labeling a molecule that achieves binding to the reagent via a ligand-receptor binding pair arrangement or other such specific recognition molecules. Detectable labels can include, but are not limited to radioisotopes, bioluminescent compounds, chromophores, antibodies, chemiluminescent compounds, fluorescent compounds, metal chelates, and enzymes.

[0258] In other embodiments, the detection reagent is label with a fluorescent compound. When the fluorescently labeled reagent is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence. In some embodiments of any of the aspects, a detectable label can be a fluorescent dye molecule, or fluorophore including, but not limited to fluorescein, phycoerythrin, phycocyanin, o-phthaldehyde, fluorescamine, Cy3™, Cy5™, allophycocyanine, Texas Red, peridenin chlorophyll, cyanine, tandem conjugates such as phycoerythrin-Cy5™, green fluorescent protein, rhodamine, fluorescein isothiocyanate (FITC) and Oregon Green™, rhodamine and derivatives (e.g., Texas red and tetrarhodimine isothiocynate (TRITC)), biotin, phycoerythrin, AMCA, CyDyes™, 6- carboxyfhiorescein (commonly known by the abbreviations FAM and F), 6-carboxy- 2',4',7',4,7-hexachlorofiuorescein (HEX), 6-carboxy-4',5'-di chi oro-2', 7'-dimethoxyfiuorescein (JOE or J), N,N,N',N'-tetramethyl-6carboxyrhodamine (TAMRA or T), 6-carboxy-X- rhodamine (ROX or R), 5-carboxyrhodamine-6G (R6G5 or G5), 6-carboxyrhodamine-6G (R6G6 or G6), and rhodamine 110; cyanine dyes, e.g., Cy3, Cy5 and Cy7 dyes; coumarins, e.g., umbelliferone; benzimide dyes, e.g., Hoechst 33258; phenanthridine dyes, e.g., Texas Red; ethidium dyes; acridine dyes; carbazole dyes; phenoxazine dyes; porphyrin dyes;polymethine dyes, e.g., cyanine dyes such as Cy3, Cy5, etc; BODIPY dyes and quinoline dyes. In some embodiments of any of the aspects, a detectable label can be a radiolabel including, but not limited to3H,1251,35S,14C,32P, and33P. In some embodiments of any of the aspects, a detectable label can be an enzyme including, but not limited to horseradish peroxidase and alkaline phosphatase. An enzymatic label can produce, for example, a chemiluminescent signal, a color signal, or a fluorescent signal. Enzymes contemplated for use to detectably label an antibody reagent include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, del ta-V- steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, betagalactosidase, ribonuclease, urease, catalase, glucose- Vl-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. In some embodiments of any of the aspects, a detectable label is a chemiluminescent label, including, but not limited to lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. In some embodiments of any of the aspects, a detectable label can be a spectral colorimetric label including, but not limited to colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads.

[0259] In some embodiments of any of the aspects, detection reagents can also be labeled with a detectable tag, such as c-Myc, HA, VSV-G, HSV, FLAG, V5, HIS, or biotin. Other detection systems can also be used, for example, a biotin-streptavidin system. In this system, the antibodies immunoreactive (i. e. specific for) with the biomarker of interest is biotinylated. Quantity of biotinylated antibody bound to the biomarker is determined using a streptavidin-peroxidase conjugate and a chromagenic substrate. Such streptavidin peroxidase detection kits are commercially available, e. g. from DAKO; Carpinteria, CA. A reagent can also be detectably labeled using fluorescence emitting metals such as152Eu, or others of the lanthanide series. These metals can be attached to the reagent using such metal chelating groups as diethylenetriaminepentaacetic acid (DTP A) or ethylenediaminetetraacetic acid (EDTA).

[0260] In some embodiments, the methods described herein relate to treating a subject having or diagnosed as having endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. In some embodiments of any of the aspects, the subj ect is a current or former patient with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. In some embodiments of any of the aspects, thesubject has been exposed to air pollution or certain chemicals. See Upson K. Environmental risk factors for endometriosis: A critical evaluation of studies and recommendations from the epidemiologic perspective. Curr Epidemiol Rep. 2020 Sep;7(3): 149-170. In some embodiments of any of the aspects, the subject has or is diagnosed as having endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis.Administration

[0261] In some embodiments, the methods described herein relate to treating or preventing inflammation in female reproductive organs in a subject in need thereof, the method comprising administering to the subject an IL-8 receptor inhibitor, e.g., reparixin. In other embodiments, the methods described herein relate to treating or preventing inflammation in female reproductive organs in a subject in need thereof, the method comprising administering to the subject reparixin. In one embodiment, the subject has been diagnosed as having or at risk of having inflammation in female reproductive organs, e.g., endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. Subjects having endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis can be identified by a physician using current methods of endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. Symptoms and / or complications of endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis which characterize these conditions and aid in diagnosis are well known in the art and include but are not limited to, painful menstrual periods, chronic pain in the lower back and / or pelvis, pain during or after sexual intercourse, painful bowel movements, pain when urinating during menstrual periods, infertility, diarrhea, constipation, bloating, or nausea, especially during menstrual periods.

[0262] In one embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having inflammation of female reproductive organs (e.g., endometriosis). In one embodiment, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of inflammation of the female reproductive organs (e.g., endometriosis). In another embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having pain of female reproductive organs (e.g.,endometriosis). In another embodiment, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of pain of the female reproductive organs (e.g., endometriosis). In another embodiment, the method further comprises the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion on female reproductive organs (e.g., endometriosis). In another embodiment, the method further comprises the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of at least one lesion on the female reproductive organs (e.g., endometriosis).

[0263] Endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, and / or adenomyosis are diagnosed using the clinical criteria of symptoms and signs typical of inflammation, pain, and / or at least one lesion of, for example female reproductive organs or any other organ or tissue described herein. Some individuals do not have any signs or symptoms. Signs or symptoms typical of inflammation of female reproductive organs include, but are not limited to pain in the lower abdomen and pelvis, vaginal discharge, abnormal uterine bleeding, pain during sexual intercourse, fever, and chills. One who is skilled in the art will be able to use the clinical criteria and identify a subject that is suffering from endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis.

[0264] Tests that may aid in a diagnosis of inflammation, pain, and / or at least one lesion of, e.g., female reproductive organs e.g., endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis include, but are not limited to, pelvic examination, ultrasound, magnetic resonance imaging, and / or laparoscopy. A family history of endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis or exposure to risk factors for endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis (e.g., age between 25 to 40 years old, hormonal imbalance, immune system problems, genetics, surgical scars from surgeries such as a Cesarean (C- section) or hysterectomy, women who have not had children, menstrual problems (i.e., heavy or shorter periods) since puberty) can also aid in determining if a subject is likely to have endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis or in making a diagnosis ofendometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis.

[0265] The compositions and methods described herein can be administered to a subject having or diagnosed as having endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. In some embodiments, the methods described herein comprise administering an effective amount of compositions described herein, e.g., a IL-8 receptor inhibitor to a subject in order to alleviate a symptom of a endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. As used herein, "alleviating a symptom of endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis " is ameliorating any condition or symptom associated with the endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, vaginal dysbiosis, or adenomyosis. As compared with an equivalent untreated control, such reduction is by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique. A variety of means for administering the compositions described herein to subjects are known to those of skill in the art. Such methods can include, but are not limited to oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, cutaneous, topical, injection, or intratumoral administration.Administration can be local or systemic.

[0266] The term “effective amount" as used herein refers to the amount of an IL-8 receptor inhibitor needed to alleviate at least one or more symptom of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect. The term "therapeutically effective amount" therefore refers to an amount of an IL-8 receptor inhibitor that is sufficient to provide a particular anti-inflammatory effect when administered to a typical subject. An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount". However, for any given case, an appropriate “effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0267] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining theLD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (z.e., the concentration of an IL-8 receptor inhibitor, which achieves a half- maximal inhibition of symptoms) as determined in cell culture, or in an appropriate animal model. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay, e.g., assay for IL-8 receptor expression or activity, among others. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0268] In some embodiments, the technology described herein relates to a pharmaceutical composition comprising an IL-8 receptor inhibitor as described herein, and optionally a pharmaceutically acceptable carrier. In some embodiments, the active ingredients of the pharmaceutical composition comprise an IL-8 receptor inhibitor as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist essentially of an IL-8 receptor inhibitor as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consist of an IL-8 receptor inhibitor as described herein. Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents and / or dispersion media. The use of such carriers and diluents is well known in the art. Some non-limiting examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate;(4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation. The terms such as "excipient", "carrier", "pharmaceutically acceptable carrier" or the like are used interchangeably herein. In some embodiments, the carrier inhibits the degradation of the active agent, e.g., an IL-8 receptor inhibitor as described herein.

[0269] In some embodiments, the IL-8 receptor inhibitor can be used at a dose between 0.1mg / kg-0.2mg / kg, between 0.1mg / kg-0.3mg / kg, between 0.1mg / kg-0.4mg / kg, between 0.1mg / kg-0.5mg / kg, between 0.1mg / kg-0.6mg / kg, between 0.1mg / kg-0.7mg / kg, between 0.1mg / kg-0.8mg / kg, between 0.1mg / kg-0.9mg / kg, between O.lmg / kg-l.Omg / kg, between O. lmg / kg-l. lmg / kg, between 0.1mg / kg-1.2mg / kg, between 0.1mg / kg-1.3mg / kg, between 0.1mg / kg-1.4mg / kg, between 0.1mg / kg-1.5mg / kg, between 0.1mg / kg-1.6mg / kg, between 0.1mg / kg-1.7mg / kg, between 0.1mg / kg-1.8mg / kg, between 0.1mg / kg-1.9mg / kg, between 0.1mg / kg-2.0mg / kg, between 0.1mg / kg-2.1mg / kg, between 0.1mg / kg-2.2mg / kg, between 0.1mg / kg-2.3mg / kg, between 0.1mg / kg-2.4mg / kg, between 0.1mg / kg-2.5mg / kg, between 0.1mg / kg-2.6mg / kg, between 0.1mg / kg-2.7mg / kg, between 0.1mg / kg-2.8mg / kg, between 0.1mg / kg-2.9mg / kg, between 0.1mg / kg-3.0mg / kg, between 0.1mg / kg-3.1mg / kg, O.lmg / kg- 3.2mg / kg, between 0.1mg / kg-3.3mg / kg, between 0.1mg / kg-3.4mg / kg, between O.lmg / kg- 3.5mg / kg, between 0.1mg / kg-3.6mg / kg, between 0.1mg / kg-3.7mg / kg, between O.lmg / kg- 3.8mg / kg, between 0.1mg / kg-3.9mg / kg, between 0.1mg / kg-4.0mg / kg, between O.lmg / kg- 4.1mg / kg, between 0.1mg / kg-4.2mg / kg, between 0.1mg / kg-4.3mg / kg, between O.lmg / kg- 4.4mg / kg, between 0.1mg / kg-4.5mg / kg, between 0.1mg / kg-4.6mg / kg, between O.lmg / kg- 4.7mg / kg, between 0.1mg / kg-4.8mg / kg, between 0.1mg / kg-4.9mg / kg, between O.lmg / kg- 5.0mg / kg, between 0.1mg / kg-5.1mg / kg, between 0.1mg / kg-5.2mg / kg, between O.lmg / kg- 5.3mg / kg, between 0.1mg / kg-5.4mg / kg, between 0.1mg / kg-5.5mg / kg, between O.lmg / kg- 5.6mg / kg, between 0.1mg / kg-5.7mg / kg, between 0.1mg / kg-5.8mg / kg, between O.lmg / kg- 5.9mg / kg, between 0.1mg / kg-6.0mg / kg, between 0.1mg / kg-6.1mg / kg, 0.1mg / kg-6.2mg / kg, between 0.1mg / kg-6.3mg / kg, between 0.1mg / kg-6.4mg / kg, between 0.1mg / kg-6.5mg / kg, between 0.1mg / kg-6.6mg / kg, between 0.1mg / kg-6.7mg / kg, between 0.1mg / kg-6.8mg / kg, between 0.1mg / kg-6.9mg / kg, between 0.1mg / kg-7.0mg / kg, between 0.1mg / kg-7.1mg / kg, between 0.1mg / kg-7.2mg / kg, between 0.1mg / kg-7.3mg / kg, between 0.1mg / kg-7.4mg / kg,between 0.1mg / kg-7.5mg / kg, between 0.1mg / kg-7.6mg / kg, between 0.1mg / kg-7.7mg / kg, between 0.1mg / kg-7.8mg / kg, between 0.1mg / kg-7.9mg / kg, between 0.1mg / kg-8.0mg / kg, between 0.1mg / kg-8.1mg / kg, between 0.1mg / kg-8.2mg / kg, between 0.1mg / kg-8.3mg / kg, between 0.1mg / kg-8.4mg / kg, between 0.1mg / kg-8.5mg / kg, between 0.1mg / kg-8.6mg / kg, between 0.1mg / kg-8.7mg / kg, between 0.1mg / kg-8.8mg / kg, between 0.1mg / kg-8.9mg / kg, between 0.1mg / kg-9.0mg / kg, between 0.1mg / kg-9.1mg / kg, between 0.1mg / kg-9.2mg / kg, between 0.1mg / kg-9.3mg / kg, between 0.1mg / kg-9.4mg / kg, between 0.1mg / kg-9.5mg / kg, between 0.1mg / kg-9.6mg / kg, between 0.1mg / kg-9.7mg / kg, between 0.1mg / kg-9.8mg / kg, between 0.1mg / kg-9.9mg / kg, between O.lmg / kg-lO.Omg / kg, between 0.1mg / kg-20.0mg / kg, between O. lmg / kg-3O.Omg / kg, between 0.1mg / kg-40.0mg / kg, between O. lmg / kg-5O.Omg / kg, between 0.1mg / kg-60.0mg / kg, between 0.1mg / kg-70.0mg / kg, between O. lmg / kg-8O.Omg / kg, between 0.1mg / kg-90.0mg / kg, between O.lmg / kg-lOOmg / kg, or more.

[0270] In some embodiments, the pharmaceutical composition comprising an IL-8 receptor inhibitor as described herein can be a parenteral dose form. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In addition, controlled-release parenteral dosage forms can be prepared for administration of a patient, including, but not limited to, DUROS®-type dosage forms and dose-dumping.

[0271] Suitable vehicles that can be used to provide parenteral dosage forms of an IL-8 receptor inhibitor as disclosed within are well known to those skilled in the art. Examples include, without limitation: sterile water; water for injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, sodium chloride injection, Ringer's injection, dextrose Injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that alter or modify the solubility of a pharmaceutically acceptable salt of an IL- 8 receptor inhibitor as disclosed herein can also be incorporated into the parenteral dosage forms of the disclosure, including conventional and controlled-release parenteral dosage forms.

[0272] Another aspect provided herein provides a composition comprising an agent that inhibits an IL-8 receptor. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a second therapeutic agent.Pharmaceutical compositions

[0273] Pharmaceutical compositions comprising an IL-8 receptor inhibitor can be formulated to be suitable for oral administration, for example as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of the disclosed compounds, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).

[0274] Pharmaceutical compositions comprising an IL-8 receptor inhibitor can also be formulated to be suitable for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation. The IL-8 receptor inhibitor can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0275] Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels. In particular, controlled- or extended-releasedosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under-dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug. In some embodiments, the IL-8 receptor inhibitor can be administered in a sustained release formulation.

[0276] Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions. Kim, Chemg-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000).

[0277] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.

[0278] In addition to the formulations described previously, the IL-8 receptor inhibitor can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the inhibitor can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0279] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate permeation. Transmucosal administration can be through the use of suppositories.

[0280] The compositions can, if desired, be presented in a pack or dispenser device which can contain one or more-unit dosage forms containing the active ingredient. The pack can for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0281] In some embodiments, the composition further comprises one or more of binders, viscosity modifiers, preservatives, humectants, emollients, pH stabilizing agents, chelating agents, gelling agents, thickening agents, emulsifiers, buffers, and carriers.

[0282] A variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the salts and compositions of the disclosure. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is incorporated herein by reference. These dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or a combination thereof to provide the desired release profile in varying proportions. In some embodiments, an extended release dosage form can be in the form of a slow-release gel, a inter-uterine device, or a vaginal suppository.

[0283] In some embodiments of any of the aspects, the methods described herein can further comprise administering a second agent and / or treatment to the subject, e.g., as part of a combinatorial therapy. By way of non-limiting example, if a subject is to be treated for pain or inflammation according to the methods described herein, the subject can also be administered a second agent and / or treatment known to be beneficial for subjects suffering from pain or inflammation. Examples of such agents and / or treatments include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs - such as aspirin, ibuprofen, or naproxen); corticosteroids, including glucocorticoids (e.g., cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone); methotrexate; sulfasalazine; leflunomide; anti-TNF medications; cyclophosphamide; proresolving drugs; mycophenolate; or opiates (e.g., endorphins, enkephalins, and dynorphin), steroids, analgesics, barbiturates, oxycodone, morphine, lidocaine, and the like.

[0284] In certain embodiments, an effective dose of a composition comprising an IL-8 receptor inhibitor as described herein can be administered to a patient once. In certain embodiments, an effective dose of a composition comprising an IL-8 receptor inhibitor can be administered to a patient repeatedly. For systemic administration, subjects can be administered a therapeutic amount of a composition comprising a IL-8 receptor inhibitor, such as, e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or more.

[0285] In some embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after treatment biweekly for three months, treatment can be repeated once per month, for six months or a year or longer. Treatment according to the methods described herein can reduce levels of a marker or symptom of a condition, e.g., endometriosis by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 % or at least 90% or more.

[0286] The dosage of a composition as described herein can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment, or make other alterations to the treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to an IL-8 receptor inhibitor. The desired dose or amount of activation can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule. In some embodiments, administration can be chronic, e.g., one or more doses and / or treatments daily over a period of weeks or months. Examples of dosing and / or treatment schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or more. A composition comprising an IL-8 receptor inhibitor can be administered over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, or 25-minute period.

[0287] The dosage ranges for the administration of an IL-8 receptor inhibitor, according to the methods described herein depend upon, for example, the form of the IL-8 receptor inhibitor, its potency, and the extent to which symptoms, markers, or indicators of a conditiondescribed herein are desired to be reduced, for example the percentage reduction desired for endometriosis or the extent to which, for example, the inflammation is reduced. The dosage should not be so large as to cause adverse side effects, such as immune suppression. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication.

[0288] The efficacy of an IL-8 receptor inhibitor in, e.g., the treatment of inflammation, lesions, and / or pain of, e.g., the female reproductive organs or any other organs or tissues as described herein, can be determined by the skilled clinician. However, a treatment is considered “effective treatment," as the term is used herein, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or a desired response is induced e.g., by at least 10% following treatment according to the methods described herein. Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and / or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g., reduction of pain and / or lesions in the female reproductive organs. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization, or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and / or are described herein. Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e.g., pain or inflammation); or (2) relieving the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease. Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response, (e.g., reduced pain and / or at least one lesion of, e.g., the female reproductive organs). It is well within the ability of one skilled in the art to monitor efficacy of administration and / or treatment by measuring any one of such parameters, or any combination of parameters. Efficacy can be assessed in animal models of a condition described herein, for example treatment of endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis. When using an experimental animal model, efficacy of treatment is evidencedwhen a statistically significant change in a marker is observed, e.g., reduced pain and / or lesions of, e.g., the female reproductive organs.

[0289] In one respect, the present invention relates to the herein described method thereof, as essential to the technology, yet open to the inclusion of unspecified elements, essential or not ("comprising”). In some embodiments of any of the aspects, other elements to be included in the description of the method are limited to those that do not materially affect the basic and novel character! stic(s) of the technology (e.g., the method thereof “consists essentially of’ the elements described herein). This applies equally to steps within a described method as well as compositions and components therein. In other embodiments of any of the aspects, the methods, described herein are intended to be exclusive of any element not deemed an essential element to the method (e.g., the method thereof “consists of’ the elements described herein). This applies equally to steps within a described method as well as compositions and components therein.

[0290] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. 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 belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0291] The invention disclosed herein can be further described in the following numbered paragraphs.1) A method of preventing or reducing inflammation associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.2) The method of paragraph 1, wherein the female reproductive organs include ovaries, fallopian tubes, uterus, uterosacral ligament, the peritoneum, and the peritoneal fluid surrounding the pelvis.3) The method of any preceding paragraph, wherein the inflammation is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.4) The method of any preceding paragraph, wherein the inflammation is not associated with cancer of the female reproductive organs. 5) The method of any preceding paragraph, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer. 6) The method of any preceding paragraph, wherein the inflammation is not associated with an ovarian cyst or uterine fibroids. 7) The method of any preceding paragraph, wherein the inflammation is associated with endometriosis. 8) The method of any preceding paragraph, wherein the inflammation is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control. 9) The method of any preceding paragraph, wherein the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity. 10) The method of any preceding paragraph, wherein the IL-8 receptor inhibitor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration. 11) The method of any preceding paragraph, wherein the IL-8 receptor inhibitor is an antibody reagent, an inhibitory nucleic acid, or a small molecule. 12) The method of any preceding paragraph, wherein the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2. 13) The method of any preceding paragraph, wherein the IL-8 receptor is CXCR1. 14) The method of any preceding paragraph, wherein the IL-8 receptor is CXCR2. 15) The method of any preceding paragraph, wherein the IL-8 receptor inhibitor is a small molecule inhibitor of IL-8 receptor. 16) The method of any preceding paragraph, wherein the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933. 17) The method of any preceding paragraph, wherein the small molecule inhibitor of IL-8 receptor is reparixin. 18) The method of any preceding paragraph, wherein the administering is systemic or local administration.19) The method of any preceding paragraph, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having inflammation associated with female reproductive organs.20) The method of any preceding paragraph, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having inflammation associated with female reproductive organs.21) The method of any preceding paragraph, wherein the subject has been previously treated for inflammation associated with female reproductive organs.22) The method of any preceding paragraph, wherein the subject has reoccurring inflammation associated with female reproductive organs.23) The method of any preceding paragraph, wherein the subject has acute inflammation associated with female reproductive organs.24) The method of any preceding paragraph, wherein the subject has chronic inflammation associated with female reproductive organs.25) The method of any preceding paragraph, further comprising administering to a subject in need thereof a second therapeutic agent.26) The method of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), another analgesic, a hormonal agent, and surgical removal of a lesion(s).27) The method of any preceding paragraph, wherein the subject is a mammal.28) The method of any preceding paragraph, wherein the subject is human.29) A method of preventing or reducing pain associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.30) The method of any preceding paragraph, wherein the pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.31) The method of any preceding paragraph, wherein the pain is not associated with cancer of the female reproductive organs.32) The method of any preceding paragraph, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.33) The method of any preceding paragraph, wherein the pain is not associated with an ovarian cyst or uterine fibroids.34) The method of any preceding paragraph, wherein the pain is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.35) The method of any preceding paragraph, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having pain associated with female reproductive organs.36) The method of any preceding paragraph, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having pain associated with female reproductive organs.37) The method of any preceding paragraph, wherein the subject has been previously treated for pain associated with female reproductive organs.38) The method of any preceding paragraph, wherein the subject has reoccurring pain associated with female reproductive organs.39) The method of any preceding paragraph, wherein the subject has acute pain associated with female reproductive organs.40) The method of any preceding paragraph, wherein the subject has chronic pain associated with female reproductive organs.41) The method of any preceding paragraph, wherein the subject has spontaneous pain associated with female reproductive organs.42) The method of any preceding paragraph, wherein the subject has chronic and spontaneous pain associated with female reproductive organs.43) The method of any preceding paragraph, further comprising administering to a subject a second therapeutic agent.44) The method of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug(NS AID), an analgesic, a hormonal agent, and surgical removal of lesion(s).45) A method of preventing or treating at least one lesion on female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.46) The method of any preceding paragraph, wherein the at least one lesion is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.47) The method of any preceding paragraph, wherein the at least one lesion is not associated with cancer of the female reproductive organs.48) The method of any preceding paragraph, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.49) The method of any preceding paragraph, wherein the at least one lesion is not associated with an ovarian cyst or uterine fibroids.50) The method of any preceding paragraph, wherein the at least one lesion is associated with endometriosis.51) The method of any preceding paragraph, wherein the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.52) The method of any preceding paragraph, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion on female reproductive organs.53) The method of any preceding paragraph, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion on female reproductive organs.54) The method of any preceding paragraph, wherein the subject has been previously treated for at least one lesion associated with female reproductive organs.55) The method of any preceding paragraph, wherein the subject has reoccurring lesions associated with female reproductive organs.56) The method of any preceding paragraph, wherein the subject has acute lesions associated with female reproductive organs.57) The method of any preceding paragraph, wherein the subject has chronic lesions associated with female reproductive organs.58) The method of any preceding paragraph, further comprising administering to a subject in need thereof a second therapeutic agent.59) The method of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug(NSAID), an analgesic, a hormonal agent, and surgical removal of the at least one lesion.60) A method of preventing or treating at least one lesion associated with endometriosis comprising administering an IL-8 receptor inhibitor to a subject in need thereof.61) The method of any preceding paragraph, wherein the at least one lesion is present on or in any organ or tissue.62) The method of any preceding paragraph, wherein the at least one lesion is present on the uterus, fallopian tubes, ovaries, intestines, rectum, bladder, uterosacral ligament, mesentery, peritoneum, liver, diaphragm, lungs, and / or surgical scar.63) The method of any preceding paragraph, wherein the at least one lesion is not associated with cancer of the female reproductive organs.64) The method of any preceding paragraph, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.65) The method of any preceding paragraph, wherein the at least one lesion is not associated with an ovarian cyst or uterine fibroids.66) The method of any preceding paragraph, wherein the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.67) The method of any preceding paragraph, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion associated with endometriosis.68) The method of any preceding paragraph, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion associated with endometriosis.69) The method of any preceding paragraph, wherein the subject has been previously treated for at least one lesion associated with endometriosis.70) The method of any preceding paragraph, wherein the subject has reoccurring lesions associated with endometriosis.71) The method of any preceding paragraph, wherein the subject has acute lesions associated with endometriosis.IT) The method of any preceding paragraph, wherein the subject has chronic lesions associated with endometriosis.73) The method of any preceding paragraph, further comprising administering to a subject in need thereof a second therapeutic agent.74) The method of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of the lesions.75) A composition comprising an agent that inhibits an IL-8 receptor.76) The composition of any preceding paragraph, wherein the agent that inhibits IL-8 receptor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.77) The composition of any preceding paragraph, wherein the agent that inhibits IL-8 receptor inhibits IL-8 receptor expression and / or activity.78) The composition of any preceding paragraph, wherein IL-8 receptor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.79) The composition of any preceding paragraph, wherein the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2.80) The composition of any preceding paragraph, wherein the IL-8 receptor is CXCR1.81) The composition of any preceding paragraph, wherein the IL-8 receptor is CXCR2.82) The composition of any preceding paragraph, wherein the agent that inhibits IL-8 receptor is a small molecule inhibitor of IL-8 receptor.83) The composition of any preceding paragraph, wherein the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933.84) The composition of any preceding paragraph, wherein the small molecule inhibitor of IL-8 receptor is reparixin.85) The composition of any preceding paragraph, further comprising a pharmaceutically acceptable carrier.86) The composition of any preceding paragraph, further comprising a second therapeutic agent.87) The composition of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NS AID), an analgesic, a hormonal agent, and surgical removal of a lesion(s).88) A method of treating or preventing inflammation, pain, or at least one lesion, the method comprising administering a composition of any preceding paragraph to a subject in need thereof.89) The method of any preceding paragraph, wherein the subject has or is at risk of having inflammation, pain, or lesions.90) The method of any preceding paragraph, wherein the subject does not have cancer of the female reproductive organs.91) The method of any preceding paragraph, wherein the subject does not have an ovarian cyst or uterine fibroids.92) Use of the composition of any preceding paragraph for the treatment or prevention of inflammation, pain or lesions.93) A method of treating or preventing at least one lesion associated with endometriosis, the method comprising administering an IL-8 receptor inhibitor to a subject in need thereof, wherein the IL-8 receptor inhibitor is reparixin.94) The method of any preceding paragraph, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having endometriosis.95) The method of any preceding paragraph, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having endometriosis.96) The method of any preceding paragraph, further comprising administering to a subject in need thereof, a second therapeutic agent.97) The method of any preceding paragraph, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of a lesion(s).EXAMPLESEXAMPLE 1:

[0292] Endometriosis is an inflammatory, estrogen dependent disease often characterized by pain and / or infertility. In endometriosis, immune-mediated inflammatory factors play an active role in the induction of pain. Reparixin is a CXCR1 and CXCR2 inhibitor preventingtheir activation via IL-8. Reparixin is expected to reduce endometriosis-associated pain by reducing immune cell migration, proliferation, and growth via CXCR1 and CXCR2 inhibition.

[0293] Results

[0294] Effect of Reparixin on lesion size and implantation

[0295] All recipient mice were injected with dissociated uterine horns as outlined. Mice were treated beginning 29 days after lesion induction and ending 56 days post tissue implantation. Mice were treated twice daily by subcutaneous injection with reparixin 25mg / kg or vehicle control.

[0296] Treatment with reparixin did not significantly reduce the percentage of mice with lesions nor number of lesions per mouse when compared to the vehicle-treated group (Fig. 1 A and C). In contrast, treatment with reparixin significantly reduced both lesion size and total lesion burden when compared to the vehicle-treated group (Fig. IB).

[0297] Effect of Reparixin on endometriosis-associated changes in thermal selection

[0298] The thermal gradient assay was performed as a measurement of the mouse own’s determination of general discomfort [1, 2], This assay uses video recordings to measure behavior in freely moving mice without the presence of a human investigator [2], Mice with endometriosis exhibited a more dispersed pattern from 21 to 40°C with no single preferred temperature (Fig. 2). Panel A shows time spent in each zone for each mouse within a group while panel B shows the group mean for the time spent in each. A best-fit Gaussian curve was applied to confirm differences in data dispersion (C). These data show reparixin treated mice exhibited noticable activity in this assay.

[0299] Effect of reparixin on endometriosis-induced spontaneous pain

[0300] A significant reduction was observed in abdominal contortions (Fig. 3 A, contraction of the abdominal muscle together with stretching of hind limbs), abdominal squashing (Fig. 3B, pressing of the lower abdominal region against the floor), and direct abdominal licking (Fig. 3C) in the reparixin treated group. Treatment with reparixin reduced endometriosis- induced spontaneous pain.

[0301] Effect of reparixin on endometriosis-associated mechanical pain

[0302] To determine abdominal mechanical pain, we conducted von Frey test. The test was conducted weekly from 7 to 56 dpi. Treatments were performed twice daily starting on 29 to 56 dpi. As expected, a reduction was observed in the mechanical threshold for both groups after induction of endometriosis starting at 7 dpi and lasting until 56 dpi (Fig. 4). Treatment with reparixin allieviated the endometriosis-associated reduction in mechanical threshold(Fig. 4).

[0303] Methods

[0304] Study design

[0305] Block randomization was used to randomize subjects into two groups. Mice were treated twice a day by subcutaneous injection with reparixin 25mg / kg (n = 9), or vehicle (10% DMSO 5% Tween-80 in Phosphate Buffered Saline) (n = 10) starting at day 29 and ending on day 56. Reparixin was purchased from invivochem. Exclusion criterea: For the von Frey test, mice that showed mechanical threshold baseline values less than 0.09g were excluded from analysis. Therefore, specifically for the von Frey test, the number of mice per group is as follows: n = 9 (reparixin treated) and n = 10 (vehicle treated). For the thermal gradient assay, mice that climbed out of the apparatus during the assay were excluded from analysis. Therefore, specifically for the thermal gradient assay, the number of mice per group is as follows: n = 8 (reparixin treated) and n = 10 (vehicle treated). The investigators were blinded to the treatment groups in all testings until the end of the experiment and analysis.

[0306] Induction of Endometriosis

[0307] Endometriosis was induced as described previously [3], Brifly, after at least one week of acclimatization, donor mice received a subcutaneous injection of 3 pg / mouse estradiol benzoate to stimulate the growth of the endometrium. Four days later, the uteri of the donor mice were dissected into a Petri dish containing Hank's Balanced Salt Solution (HBSS, Thermo Fisher Scientific, Waltham, MA, USA) and split longitudinally with a pair of scissors. Uterine horns from each donor mouse were minced with scissors and scalpel one at the time, ensuring that the maximal diameter of each fragment was consistently smaller than 1 millimeter (mm). Each dissociated uterine horn was then injected intraperitoneally using an 18G needle (cat #305185 Thin wall, BD, Franklin Lakes, NJ, USA) into a recipient mouse in 500 pL of HBSS. One donor mouse was used for every two endometriosis mice.

[0308] Behavioral testing

[0309] Mice were allowed to habituate to the apparatus for at least 2h and during three consecutive days before the beginning of measurements. After habituation, baseline measurements were obtained one day prior to the induction of endometriosis. Pain intensity to a mechanical stimulus (mechanical hyperalgesia) in the abdominal region was measured using von Frey filaments. The experimenter was trained, and care was taken not to stimulate the same point consecutively, and the stimulation of the external genitalia was avoided. A jump or paw flinch was considered a withdrawal response [4, 5], The mechanical threshold was determinedby the up and down method starting with 0.4g filament and calculated using the open-source software Up-Down Reader [6],

[0310] For the thermal gradient assay, a continuous temperature gradient (4-50 °C) was established along with a metallic base plate where the mice were gently placed. Mice then walked freely while being video-recorded from above (Bioseb, France) as described previously [2], After an exploration period (30 minutes), individual mice showed a distinct preference, indicating the most comfortable temperature range. Data are presented by the time spent (in seconds) on each zone set at specific temperatures during 60 min. For each treatment, the best- fitted Gaussian curve was also applied to have a better readout of data dispersion. Each run lasted 1.5 h, and two mice were simultaneously recorded in separate corridors.

[0311] For spontaneous abdominal pain measurements, licking of the abdomen, stretching the abdomen (abdominal contortions), and squashing of the lower abdomen against the floor were quantified as previously described [4, 5, 7], Briefly, direct abdominal licking was quantified during using bottom-up video recording. The number of times the mouse directly groomed the abdominal region without going for any other region before or after the behavior were counted. For abdominal contortions, mice were placed in individual chambers in a temperature- controlled (29 °C) glass plate and the number of abdominal contortions was quantified with a positive responses consisting of a contraction of the abdominal muscle together with stretching of hind limbs. For abdominal squashing, the number of times the mice pressed the lower abdominal region against the floor was determined. In all testing, the investigators were blinded to the treatments.

[0312] Lesion size

[0313] Lesions were carefully dissected at 56 dpi and measured using calipers. Lesion size is expressed in millimeters (mm) calculated from the mean of two measurements (width and height).

[0314] Statistical analysis

[0315] Results are presented as mean ± SEM. Data were analyzed using the software GraphPad Prism version 9.01 (GraphPad Software, San Diego, CA, USA). Two-way repeated measure analysis of variance (ANOVA), followed by Tukey’s post hoc, was used to analyse data from mechanical hyperalgesia. An unpaired T-test was used to analyse data from experiments with a single time point. For the percentage of mice with visible lesions, statistical analysis was estimated by the Kaplan-Meier method followed by the logrank test. For all analyses, statistical differences were considered significant when p < 0.05.

[0316] References1. Touska, F., et al., Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Temperature (Austin), 2016. 3(1): p. 77-91.2. Alexandre, C., et al., Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat Med, 2017. 23(6): p. 768-774.3. Fattori, V., et al., Non-surgical mouse model of endometriosis-associated pain that responds to clinically active drugs. Pain, 2020.4. Gonzalez-Cano, R., et al., sigmal receptors are involved in the visceral pain induced by intracolonic administration of capsaicin in mice. Anesthesiology, 2013. 118(3): p. 691-700.5. Laird, J.M., et al., A new model of visceral pain and referred hyperalgesia in the mouse. Pain, 2001. 92(3): p. 335-42.6. Gonzalez-Cano, R., et al., Up-Down Reader : An Open Source Program forEfficiently Processing 50% von Frey Thresholds. Front Pharmacol, 2018. 9: p. 433.7. Fattori, V., et al., Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF -kappaB activation. Inflamm Res, 2015. 64(12): p. 993-1003.EXAMPLE 2:

[0317] Sequences

[0318] SEQ ID NO: 1 (CXCR1 genomic sequence, NG_011814.1 : 5032-9153):ACTCTGATCTCTGACTGCAGCTCCTACTGTTGGACACACCTGGCCGGTGCTTCAGGTAGGAAGCCACCTCTGTTT GCTAGGACTTTCTGTGGGGTAGGGCTGCTTGGCTTGACTTTATTTTGGAAAATGTATTCATTTCTGTGGGAGCTG AGGATTTCTGCTGCCCGCTTCCTCTCTTGTGACCACCACTCATACATGGAGTTAGCAGGTGAAGAGGACAGCCTC CTCATCCCCTCTTTTTATACCTTGCCCTTTTGTGGGAAGAGGCTGACCATTCCCCAATTTGATGTTTATTGCTTC ACCTTAAGACTTTGTCTTCAGTGAAAATGCAAATACTGGTAGGGAGGGAACACACTAAAATGTGTGGATCTGAGT GGACTCATCATACACCCTCAGGCCTGGCAGCAAATGAGAGGTGGATGATTCTGTCTTCCTCGATTTGCAGATGAG AAGAC T GAAAT CTATAGGGGTACGAGACCCCACT C AAGGT CAT GAGAC T T AT T T AT T T AT T T AT T T AT T T AT T T T GAGATGGAGTCTCACTCTGTCGCCTAGGCTGTAGTACTGTGGCACGATCTCGGCTCACTGCAACCTCCATTTCCC GGGTTCAAGTGATTCTCCTGCCTCAGCCTCCTGAGTAGTTGGGATTACAGGTGCACGCCACCACACCCAGCTAAT TTTTTTGTATTTTTAGTAGAGACGGGGTTTCATCATTTTGGTCAGGCTGGTCTCGAACTCCTGACTTCATGATCT GCCTGCCTTGGCCTCCCAAAGGGCTGGGATTACACACGAAACTTATTAATGGTAGAATCAGGATGGAATGAAGAC TGGATGCTAGGTGTCTTTACAACCAACCTCGGTGACTTTCCAAAGGCTTTCAGACTTCTCTGGAGAGTCCTGGAG CTTTGAGGGGCTCTTTAGGGGCCATCTGGGTTCGGAGATTAGCACACTCTGCCCCACAGTGGCTCAGCTTTTATC TGCTTCACATACTGGGCTTCTGGGAAGATCTTATTTCAGTAAACTATTTCACAATAGGAAATATATTTGAAAACT CTTGAATGATTCTGTGGATTTTTTCAGGGGTGGAGGGTTTCAGGGACCAAGATGGAGACTTTATCTTCTCAAATA CTTAAAACTCCTTTAGACAGAGGAACAAAATATGTGCTCCTCATTTAAAGAAGGCTTAAAATATACAGTTTAATG CAAT GT GT T GT TAT CACT T C CT T C C CC CAGT AGAT T T T AAGGAGGGT AAACAAGAAT CAGGGAGAACAT AGGAAT AGAAATAGTAGAAGGGGACACCTGGGAACAGGTTTGCCTTCTTGCATTTTGCTTAATGCTGGCCCTTCCCTGAAT GT CT AAGAC CAAC CT GGT C C C CACAT C CAAAT GCACAGACACAGCT GAGGAT GGAGAAGGCT AAAGAGGGACAGA GGT AGAGACAT AGGCT GAGAGGAGGCAGT T GT AGGT T GAGCTAGGGCT AAGGT GT T T T C C C CAT AT T C CAT CT TA C C C CACACT CAGGC CAGGC CT T AGAGT T GT GGAAGGT GGAGAACACT GGGAAGC CAAC CT C C GAAGAAGAC CAGG TTGGAGTCAAAGGAGGAAGGAGAGCTCTCATTGCCAAACCAACAGGGAAGCCAAGGATATCCCAGTAACTGCTCT CACATCATTGATGAGAATGCCTTGAATCCGAGCTACTAAATCACATTTCCTTCCTTCTAACCTTCCAGTTAGATC AAAC CAT T GCT GAAACT GAAGAGGACAT GT CAAAT AT T ACAGAT C CACAGAT GT GGGAT T T T GAT GAT CT AAAT TTCACTGGCATGCCACCTGCAGATGAAGATTACAGCCCCTGTATGCTAGAAACTGAGACACTCAACAAGTATGTTG TGATCATCGCCTATGCCCTAGTGTTCCTGCTGAGCCTGCTGGGAAACTCCCTGGTGATGCTGGTCATCTTATACA GCAGGGTCGGCCGCTCCGTCACTGATGTCTACCTGCTGAACCTGGCCTTGGCCGACCTACTCTTTGCCCTGACCT TGCCCATCTGGGCCGCCTCCAAGGTGAATGGCTGGATTTTTGGCACATTCCTGTGCAAGGTGGTCTCACTCCTGA AGGAAGTCAACTTCTACAGTGGCATCCTGCTGTTGGCCTGCATCAGTGTGGACCGTTACCTGGCCATTGTCCATG CCACACGCACACTGACCCAGAAGCGTCACTTGGTCAAGTTTGTTTGTCTTGGCTGCTGGGGACTGTCTATGAATC TGTCCCTGCCCTTCTTCCTTTTCCGCCAGGCTTACCATCCAAACAATTCCAGTCCAGTTTGCTATGAGGTCCTGG GAAATGACACAGCAAAATGGCGGATGGTGTTGCGGATCCTGCCTCACACCTTTGGCTTCATCGTGCCGCTGTTTG TCATGCTGTTCTGCTATGGATTCACCCTGCGTACACTGTTTAAGGCCCACATGGGGCAGAAGCACCGAGCCATGA GGGTCATCTTTGCTGTCGTCCTCATCTTCCTGCTTTGCTGGCTGCCCTACAACCTGGTCCTGCTGGCAGACACCC T CAT GAGGAC C CAGGT GAT C CAGGAGAGCT GT GAGC GC C GCAACAACAT C GGC C GGGC C CT GGAT GC CACT GAGA TTCTGGGATTTCTCCATAGCTGCCTCAACCCCATCATCTACGCCTTCATCGGCCAAAATTTTCGCCATGGATTCC TCAAGATCCTGGCTATGCATGGCCTGGTCAGCAAGGAGTTCTTGGCACGTCATCGTGTTACCTCCTACACTTCTT CGTCTGTCAATGTCTCTTCCAACCTCTGAAAACCATCGATGAAGGAATATCTCTTCTCAGAAGGAAAGAATAACC AACACCCTGAGGTTGTGTGTGGAAGGTGATCTGGCTCTGGACAGGCACTATCTGGGTTTTGGGGGGACGCTATAG GATGTGGGGAAGTTAGGAACTGGTGTCTTCAGGGGCCACACCAACCTTCTGAGGAGCTGTTGAGGTACCTCCAAG GACCGGCCTTTGCACCTCCATGGAAACGAAGCACCATCATTCCCGTTGAACGTCACATCTTTAACCCACTAACTG GCTAATTAGCATGGCCACATCTGAGCCCCGAATCTGACATTAGATGAGAGAACAGGGCTGAAGCTGTGTCCTCAT GAGGGCTGGATGCTCTCGTTGACCCTCACAGGAGCATCTCCTCAACTCTGAGTGTTAAGCGTTGAGCCACCAAGC TGGTGGCTCTGTGTGCTCTGATCCGAGCTCAGGGGGGTGGTTTTCCCATCTCAGGTGTGTTGCAGTGTCTGCTGG AGACATTGAGGCAGGCACTGCCAAAACATCAACCTGCCAGCTGGCCTTGTGAGGAGCTGGAAACACATGTTCCCC TTGGGGGTGGT GGAT GAACAAAGAGAAAGAGGGT T T GGAAGC CAGAT CT AT GC CACAAGAAC C C C CT T TAG C C C C AT GAC CAACAT C GCAGACACAT GT GCT GGC CAC CT GCT GAGC C C CAAGT GGAAC GAGACAAGCAGC C CT T AGC C C TTCCCCTCTGCAGCTTCCAGGCTGGCGTGCAGCATCAGCATCCCTAGAAAGCCATGTGCAGCCACCAGTCCATTG GGCAGGCAGATGTTCCTAATAAAGCTTCTGTTCCGTGCTTGTCCCTGTGGAAGTATCTTGGTTGTGACAGAGTCA AGGGTGTGTGCAGCATTGTTGGCTGTTCCTGCAGTAGAATGGGGGCAGCACCTCCTAAGAAGGCACCTCTCTGGG TTGAAGGGCAGTGTTCCCTGGGGCTTTAACTCCTGCTAGAACAGTCTCTTGAGGCACAGAAACTCCTGTTCATGC CCATACCCCTGGCCAAGGAAGATCCCTTTGTCCACAAGTAAAAGGAAATGCTCCTCCAGGGAGTCTCAGCTTCAC CCTGAGGTGAGCATCATCTTCTGGGTTAGGCCTTGCCTAGGCATAGCCCTGCCTCAAGCTATGTGAGCTCACCAG TCCCTCCCCAAATGCTTTCCATGAGTTGCAGTTTTTTCCTAGTCTGTTTTCCCTCCTTGGAGACAGGGCCCTGTC GGTTTATTCACTGTATGTCCTTGGTGCCTGGAGCCTACTAAATGCTCAATAAATAATGATCACAGGAATGAA

[0319] SEQ ID NO: 2 (CXCR1 mRNA sequence, NM 000634.3): actctgatct ctgactgcag ctcctactgt tggacacacc tggccggtgc ttcagttaga61 tcaaaccatt gctgaaactg aagaggacat gtcaaatatt acagatccac agatgtggga121 ttttgatgat ctaaatttca ctggcatgcc acctgcagat gaagattaca gcccctgtat181 gctagaaact gagacactca acaagtatgt tgtgatcatc gcctatgccc tagtgttcct241 gctgagcctg ctgggaaact ccctggtgat gctggtcatc ttatacagca gggtcggccg301 ctccgtcact gatgtctacc tgctgaacct ggccttggcc gacctactct ttgccctgac361 cttgcccatc tgggccgcct ccaaggtgaa tggctggatt tttggcacat tcctgtgcaa421 ggtggtctca ctcctgaagg aagtcaactt ctacagtggc atcctgctgt tggcctgcat481 cagtgtggac cgttacctgg ccattgtcca tgccacacgc acactgaccc agaagcgtca541 cttggtcaag tttgtttgtc ttggctgctg gggactgtct atgaatctgt ccctgccctt601 cttccttttc cgccaggctt accatccaaa caattccagt ccagtttgct atgaggtcct661 gggaaatgac acagcaaaat ggcggatggt gttgcggatc ctgcctcaca cctttggctt721 catcgtgccg ctgtttgtca tgctgttctg ctatggattc accctgcgta cactgtttaa781 ggcccacatg gggcagaagc accgagccat gagggtcatc tttgctgtcg tcctcatctt841 cctgctttgc tggctgccct acaacctggt cctgctggca gacaccctca tgaggaccca901 ggtgatccag gagagctgtg agcgccgcaa caacatcggc cgggccctgg atgccactga961 gattctggga tttctccata gctgcctcaa ccccatcatc tacgccttca tcggccaaaa1021 ttttcgccat ggattcctca agatcctggc tatgcatggc ctggtcagca aggagttctt1081 ggcacgtcat cgtgttacct cctacacttc ttcgtctgtc aatgtctctt ccaacctctg1141 aaaaccatcg atgaaggaat atctcttctc agaaggaaag aataaccaac accctgaggt1201 tgtgtgtgga aggtgatctg gctctggaca ggcactatct gggttttggg gggacgctat1261 aggatgtggg gaagttagga actggtgtct tcaggggcca caccaacctt ctgaggagct1321 gttgaggtac ctccaaggac cggcctttgc acctccatgg aaacgaagca ccatcattcc1381 cgttgaacgt cacatcttta acccactaac tggctaatta gcatggccac atctgagccc1441 cgaatctgac attagatgag agaacagggc tgaagctgtg tcctcatgag ggctggatgc1501 tctcgttgac cctcacagga gcatctcctc aactctgagt gttaagcgtt gagccaccaa1561 gctggtggct ctgtgtgctc tgatccgagc tcaggggggt ggttttccca tctcaggtgt1621 gttgcagtgt ctgctggaga cattgaggca ggcactgcca aaacatcaac ctgccagctg 1681 gccttgtgag gagctggaaa cacatgttcc ccttgggggt ggtggatgaa caaagagaaa 1741 gagggtttgg aagccagatc tatgccacaa gaaccccctt tacccccatg accaacatcg 1801 cagacacatg tgctggccac ctgctgagcc ccaagtggaa cgagacaagc agcccttagc 1861 ccttcccctc tgcagcttcc aggctggcgt gcagcatcag catccctaga aagccatgtg 1921 cagccaccag tccattgggc aggcagatgt tcctaataaa gcttctgttc cgtgcttgtc 1981 cctgtggaag tatcttggtt gtgacagagt caagggtgtg tgcagcattg ttggctgttc 2041 ctgcagtaga atgggggcag cacctcctaa gaaggcacct ctctgggttg aagggcagtg 2101 ttccctgggg ctttaactcc tgctagaaca gtctcttgag gcacagaaac tcctgttcat 2161 gcccataccc ctggccaagg aagatccctt tgtccacaag taaaaggaaa tgctcctcca 2221 gggagtctca gcttcaccct gaggtgagca tcatcttctg ggttaggcct tgcctaggca 2281 tagccctgcc tcaagctatg tgagctcacc agtccctccc caaatgcttt ccatgagttg 2341 cagttttttc ctagtctgtt ttccctcctt ggagacaggg ccctgtcggt ttattcactg 2401 tatgtccttg gtgcctggag cctactaaat gctcaataaa taatgatcac aggaatgaa

[0320] SEQ ID NO: 3 (CXCR1 protein sequence, NM_000625.1):MSNITDPQMWDFDDLNFTGMPPADEDYS PCMLETETLNKYVVI IAYALVFLLSLLGNSLVMLVI LYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWI FGTFLCKVVSLLKEVNFYSGI LLLACI SVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHPNNSS PVCYEVLGNDTAKWRMVLRI LPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRAMRVI FAVVLI FLLCWLPYNLVLLADTLMRTQVIQESCERRNNI GRALDATE I LGFLHSCLNPI IYAFI GQNFRHGFLKI LAMHGLVSKE FLARHRVTSYTSSSVNVSSNL

[0321] SEQ ID NO: 4 (CXCR2 genomic sequence, NG_052975.1 :5739-16962):AGAGACAGAAGGT GGAT AGACAAAT CT C CAC CT T CAGACT GGT AGGCT C CT C CAGAAGC CAT CAGACAGGAAGAT GTGAAAATCCCCAGCACTCATCCCAGAATCACTAAGTGGCACCTGTCCTGGGCCAAAGTCCCAGGACAGACCTCA TTGTTCCTCTGTGGGAATACCTCCCCAGGAGGGCATCCTGGATTTCCCCCTTGCAACCCAGGTCAGAAGTTTCAT CGTCAAGGTTGTTTCATCTTTTTTTTCCTGTCTAACAGCTCTGACTACCACCCAACCTTGAGGCACAGTGAAGAC ATCGGTGGCCACTCCAATAACAGCAGGTAGGTGACTTGTTCAGTCTGAGATGCTGGCAACATATTTCTAATGGAA GAGATCTGGAAACTTCAGCCTCCTCTGAGGCCCCTGAGAACTGGGGTGATGAAGTGTAGAAGCTTAGAGCTAAAG ACAACTAAGTCTTCACCTAGACAGTGTTGCACAAAAGAATTTTCTGCAATAATAGAAATGTCCTAGACCTGCCCT GCCCAGTATGGTAGCCACTAGTCACACGTGGCCACGGAGCACTTGAAATGTGACTAGTGTGACTGCGGATCTCAA TTTTTATTTCATTTTATTTTATTTTATTTTTTCTTTTTTGAGACAGGCTCTCACTCCAATGCCCAGGCTGGAGTG CTGTGGCATGATCTTGGCTCATTGCAACCTCAACCTACAGGTCTAGGTGATTCTCCCACCTCAGCCTCCCAAGTA GCTGCAGCTACAGGCATGTGCCGCTACACTCAGCTAATTTTTTGGGTTTTGTTTGTTTGTTTGTTTTGTTTTTGT TTTTGTAAAGACAGGGTTTCGTCATGTTGCCCAGGCTGATCTCAAACTCCTGGGCTCAAGCGATCCGCCCACCTC GGCCTCCCAAAGTGCTGGGATTACAGGCATGGGCCACCTTGCCTGGCCTTTATTTTAATTAATTTTAATTTAAAT AGCTACACATGGCTAGTAGCTAGCATGCTGAACAGAATAGAATTAGAAGAAGCTCCCGTTTTCCAAAGGCACACA ACAAGGC C CAGAAAGAAT GACT T CT CCAAGCAGGAT T AGAAGC CAGGT TTTTGTTTTGTTTTTGTTT GAGACAGG GTTTTGCTCTGTCGCCCAGGCTGGAATGCAATGGCACAATCTCGGCTCACTGCAACTTCTGCCTCCCGAGTTCAA GCAATTCTTATGCCTCAGCCTCTGGAGTAGCTGGGATTACAGGCGTGCGCTGCCACGCCTGGCTAATTTTTGCAT TTTTAATAGAGGCGGGGTTTCACCATGTTGGCCAGGCTGTTCTGTAACTCCTGGCCTCGAGTGATCCACTCACCT CAGC CT C C CAAAGT GCT GGGAT T ACAGGCAT GAGC CAC C GCAC CAGAAGC CAGT T T T T T AAT T CACT C CAC C CT G CAT AT AAC C GCAGT GAT CT C CAT GGAAAT GAAAT T GAC CT AAGGAGCAT GAAGAAGGAGGCT GACT GGGAAAT GT CAAATCTGGGCTCCCCTCTCTACATCCTTTGTATCTGACTTTCTGGGACACAGGGAGGTACCTAATGGAGCTCAG AAACTTTAGGCTGGGATCCTGCTCCTTATTACAGTGAACAGGAGATAGGATTTGAGAGCAGATTTTTAGAAGTTT TTTAAACTGAAAACCTAGTTCAGCTGTGTCACTCTAGGTATGTTGCTTAACCTCTCAGAGTCTTCATTTCCTCTT CCAGAAAGTGCCTGCTTCGTGAGGTTATCCTGAGGATTAATTGATACAAATTCTGGAAAGCACTTTGCCCAGAAG C T AGAAC CTGGTAGACACT C AAC AT T AC AGC T AAT AT GAC AAT T AAT AT C CAGGT CAAAGT AAAT T AGAT GT CAT CAAAGTCAGCCTTGAAAGCAGACCCACTGCCGACTGCTTTCCCTTGACTGGGGATGTAGTGAGAGAGGCAGCATG T TAT CAGT GAAT AAAC T AT T C CAGT AAT AAT GAT C AC AAC AAT AAAGGT T AAC AT TGTACTTTATGTATGTTTTA C GT GAT T T ACAAGCAAT C C CT CAT T T CAT C CT CAC CACAAC C C CAT GAGT T GGAT T CT GT AT T GGC C C CAT T T T A CAGATGAGTAAACTGAGACTCAGAAAGGAAAAGTCACTTGCCCAGAATTGCTCAGCTAGCCCTGGTGTCATCTGC CTCTCTCCATATGTAATAAGCCTCTATCTGGTTTTAGCATCAACTGGCCAGGTGGCATTGCATTCTTCCCCAGCT TGGGAAAGAGAGGTGACAAAGACTAAGAAACATTTGCTGAACAGTTGGACTCAAAGATTCTTTCTTTGGGGTAGG CAGGCAAT T T AAGT GC GT CT GC CACAGGGAT T GAGT CCCCTCTGGGC C CT GGGAT GCAT GGAGCAAGAGAT AGGG T AAGGAAT AAT GGAGGGGAT T GAGGT GT T GT T CACT GGGGT GGGCACT T GT GAGACAGCAGAAT T AGT GT T CAT GGCTCTGCCTGGATTAATTCATTCATTTGTAATCAATAGCAAATTGATAAAATACATTCTTAGGGTCACTTAACAT TGTTTTTAAAAATGCATTTGGACTTTGGTGGAATCTTCCCTTTTACCAAAAGGCTTTCTTTCCAAATTAGAGGGT CTTGGCTCCAAGGGTGGTAAGCTGCTGCAGAGTTGGTGTCCTCAGACCCAATGCCAAGTGTGCGAAACAAGAAAG AAT AT CAAT AC C CAGAGAT GGACT T GT GGT CAGAGCAGAT GGT T GGGGAGT GAGGGGAAAGACAAGAGGCAGGAG T GGGGC CAAGAAGT AGAGGCAT CAGGT C CAGGGAGGAAC GC CAC CAGACT CAC CAGAAGCT T T AGT C CAT CT CT G TCATTTTAATGCACTGCTCCCTTTGACATGTGAAAGACATTGAAGGCTATAGTACTGCCAATGGTATGATGGGGA AGCCT GAGGCAGCT GGAAT GCCAGGAGACT CAGACAAGGCAGCT GAAGGAGCCAGCGGCT CT GAGATACAGCAAA GAT GAAAGAAAT C CAT GCAAT C CT GGGCAAGC CAT TTCCTTTGGGCTT CAGT T T C C C CAT CT GT AAAAT GGAAAG ACTAGGTAGAAAACCCCTCAGGTCCCTTCCCAATATAAACTCTACGAGTCTATGAAATGACTATGCATCCGAGAG CTGATCTGGGAACTAATTATTCAAAGTTATCAAAATCACCCGCACCCTCAGGAGCTCCACCCCTGAATTGCATTG AGCAATCTAATCTACCACTCACTTCCTCCACTGTGTTCTCACCACCACCTCCCTTTCATAGGTCACAGCTGCTCT TCTGGAGGTGTCCTACAGGTGAAAAGCCCAGCGACCCAGTAAGTCTTGGAACACCCACCCTTCCCACCAGCTAGA ATGTCTCTGTTCTCTGTTTCCCTTGATACCCAGCCTACATTTATCCTAAGCATCTCTCCCCACCCTTGGTGGGCC CCTCACCCTCACCCCTTGGCCTCTTCATTTTCTCCCTTTGGGGCTCTCCATCCCCAAAGGAAGAACTTCTGTTCC TCCTCCCTCACAACCCTCTCCAACCACTCAGGGCCACTTGCTGCCCATGCTTTTCCCTTGGCCTGGCAGCCTTCC AAGACTCAGCCAGCCCTCCTGGCCTGGGCTAGGACTGGGTCTGAGGATGGGCCGAACACTGTTCGCTTCCCACTT CCCGACACTAAATGCAATATTTGTGGATTATATTTATAGAGAGAAAGAATACTGGAACTGTACTAAAATGACTCT TTTGTTGTTAAAAAGATTGCCTTAGATGTTTGAGATCTTGTAAATGTCTCTCGTTCTATAGCATTTTCATGTAAT AAATTAGAATTCATGCCATCATCTATGGAGTTTCCAAACTACCATGAGTCACTAAGGGGCTGGCATTTTCCCTAA GT CAAGGAAGCT C C CT T T T TAT C CT GGAAT AT AT GACT GT GT GGT CAGC C GGAC C CAGC CAGT T CAAGGGT GT T T GGTTTATCATCCCTGCAAGAGCTGTTTCTTTCATTCTGGGCCAAAGAAACGGCAAAAGAAAACAATGCATAAAAC AT GAAAGAAT GT GAGT GGAC CAT AT ACAGGT T GAT T T AAT GAT AT CT CAAGAACT T AGCT T T GCT GGGCAC GGT G GCTTACACCTGTAATCTCAGCACTTTGGGAGGCTAAGGTGGGCGGATCACCTGAGGTCAGGAGTTCGAGACCAGC C C GAC CAACAT AGT GAAAC C C C GT CT CT ACT AAAAT ACAAAAAT TGGCCGGGT GCAGT GGCAGGC GC CT GT AAT C TCAGCTACTTGGGAAGCTGAGGCAGGAGAATCACTTGAACCCGGGAGGTGGAGGTTGCAGTGAGCCGAGATCACG C CAT T GCACT C CAGC CT GGCAACAGAGC GAGACT GCAT CAAAAAAAGAAAAAAAGAAAGAAAAAGAGAACT T AGC T T ACAAAT AT GT T T AAT AGAT GAGGT GCACT T T T T T T AAGAGGAAGGGCT AT AGACT ACAAAT AAGGCAAGT GT A GTCCTTTATACCTCACTGGAACAGTGGTTTCACCACTTCTCCACCCTGTGATCGCAGGCTGGTTACTGAGCCTCC CTGTTAGGTCAGCTGATCCTCCTTGTGCCTCAGTCTTCTAGAAACAGGGCCTAATTGTATCTATTTGTAATGAGC CATGGAGATCATGTACCTGTGAGGCACAAAGCAGACCTCAGATGTGTCATCTCCTTCCCTTAGTTTGTCCCTCTA ACTGCCAAGTCATCCTCTGTAGAGATTGGTAAACTAAAAAACAACACCAACAACAAACACCCCTCTCCCTACCCT AGGAGCTGGAGGTCACTGGCCTGACCTGGTTCTCCTTGCTGAGTTCTCTACCTTCTGTCCTGACTTGCATGCTCT CCCTCTGGAACCTGAAGCTGACCCATAATGCCTGGGAGCATGAGCTCACCCATACACCTCCAGCCCACCCCCAGC ACAGCTGAGCACTGGATTATCCACAGTGAGGATTTACCTGTGAAACATGCTCTGCCACTGCTGCCTGTGCTGACA TGGCAGTTTCTGCAGCAGCCTCAGTCCTGGCTTCTCACAGCCAATATTCATACATACAAGGCCCTGCTCTCTAAG AGCACAAGCTCTCTGCACCCAATATGCCCTACATCTACTCTCAAAGATGGGTCTTCTGTTGGGTCATTTGTTCCC TTAAGAGCATCTGTAATCATCTGCTCCCAGAAGTGATCCACCCTTGACCTCTTGACTTCATTGGACATACCCTGG GCCTCTCAGCAAACTTGCTCTCAACCATGGGACTGAGGAGCTGGTGACTTCTTTCAGGTCTTGCTGACCATACTG GTCCAGCAAGCTGTATTCCCAGCCCTCTCAATACCTCCCCAGCCTTCTGGCCAGGCAGGGCCAGAAATGAGGGAT T GC T T AT AAAT TAG GT AAGAC AT AC AT AAAGT AC AAT GTTAACTTTTTTTTTTTTTTTTTTGAGACGGAGTCTCC TCTGTCGCCCAGGCTGGAGTGCAGTGGCGCCATCTCGGCTCACTGCAAGCTTCGCTTCCCGGGTTCACACCGTTC TCCTGCCTCAGCCTCCCGAGTAGCTGGGACCACAGGCGCCCGCCACCACGCCCAGCTAATTTTTTGTATTTTTAG TAGAGACGGGGTTTCACTGCATTAGCCAGGATGGTCTCGATCTCCTGACCTCATGATCCGCCCATCTCGGCCTCC CAAAGT GCT GGGAGC CAC CAC GC C C GGC C CAAAT GT T AACT T T TAT T GT T GT GAT CT AGT AT AGT AC AT T ACAAC TGATTGAATCTTCTCCATCAGTTGCCTCGGCATGCTGGGAAGGCAATGTATCTGGCCCCTAACTCTTAAAAGAGA AACTAAAAACTTGTCAGGAAGGTGATGGCTAAGAATTCCATCACTCTTGGGGGAAAAGTGGCATTATTTTTCCAG TTTTGCTTAATCTTCTTCAGCTTTCTTCTTTGCTACATATGATTGATGACAACAGAGACTTCCTTTCTGCTAAAA AGAAATCCTCCCTGGGACTTTTGTTGTTATTTTTGTAATATTTGTATTTGCTTTGCAAGGCCGTGTACCCTTTGA T T AAT CTTTTTTT T AAT T AAGAC AT AAGT CAC AT AC C C C AAAAGT C AC C CAT T T AAAGT T T T T AGC AT AT T C T AC AACCATTGCCACTAATTCCAGAACACTTTTATCACTCAAAAGAAAAACTCCGTAGTCATTAACATTCCTCTCCCA GCTCCCCTTGACCCTGGAAACCACCAATCTACTTTCTGTCTCTACCAATTCTACCCATTTGCCTATTTTGGTCAT TTCACATATATGGAATCACACAATAAGAAAACTTTTGTGTCTGCCTTTTTTCACCTAGACTAACATTTTCAAGGT TCATCCATGTTGTATTGTGTATCAGTACCTCATTCCTTCTCATGGCTGAATAATATTCTGTTGTACATAATACAG T CAT AAGT T GCT T AACAAT GC GGAT GCAT T CT GAGAAAT AT GT CAT GT GAACAT GGT AGAGT AT AC GAT GCT AT A GCCTACTACACACAT GGGCTATAT GGT AGAGT ACT GCT CCTAGGCTACAAACCTACT CAGCAT GTTACT GTACTA AAT AC T GT AGGT AAT T AT AAC AC AAT GGT AT T C T T AT AT AT AAAC AT AGGAAAAGAAC AC T AAAAAT AC AGT AT T ATAATCTTATGGGACCACTGTGGTATTTGTGATGTGTCATTGACCAAAAAGTCTTTCAGTTGCTCATGACTGTTC CTCAATTTGTCTGTCCGTTCATCAGTTGATGGATATTTGGTTTGTTTCCACTTTTTGGCCTTAATGATGAATGCT ACTATGAACATTAGCTTTCAATTCTCTTGGGTGTATACCTAGGTTGGGGTTTGCTGGTTCATGTGGTAACTCTAT GTTTAACTTTTTTGAGCAACTGCTAAGCTGTTTTCCAAAGCAGCTGCACCATCTTACATTCCCACCTGCAATGTG GGAGAGTTCTGACTTTTCCACTTCCTCACCCACATTGTTCTTGGGCATCTTTTTCTGAGTGTGCCCAGCCTGGTGAGTGTGAAGTGGGTTCTGGGACCTTTAACTTCCTGGTTTTTCTCTCACACTGGGTTCCATTTTGGGGGTAGATTA CGGACTTGGACATGGTTGGTGGTAGGGTGGTCATCCCTTACTCTAAGGCAATGGCCGGAGGGTGATCTATTTTGT GGTTCAGAAAGAAGCTAATTAGGGAGCTGGATTGCTTTAGTTGACTGCTTTGAGAAACTGGGATTTTTTTTTTTTTTTTTTTTTTTTTTTGAGGCAGAGTCTCGCTCTGTTGCCCAGGCTGGAGTGCAGTGATGTGATTTCGGCTCACTG CAACCTCCACCTCCTGGGTTCAAGCAATTCTTGTGCCTCAGCCTCCCAAGTAGCTGGGATTACAGGTGCACGTCA CCATACCTGGCTAATTTTTGTATTATTAGTAGAGACAGTGTTTCACCATGTTAGCCAGGCTGCTCTCAAACTCCT GACCTCAAGTGATCTGCCACCTCAGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACTGGGATAATATT TTTGAATAACTGCAGCCCACCCTCCACACCCAGGCTTCCCCAGAGCAGGATCTGTGCTGTCCCTGTGGCAAGGGC AGAGCCCCAGGAGCTAGACTAAATCTGAGAGGAACAGGGGAGTCAAGGCTAGATGGAGGCACACACATGCAGGAC AGGAAGGGTCTCCAGCAGGGCTGGAAAGCCACCAAGCAAGGGTAGTGCAAACCCTGTCTTCTCTGCTTCCTGCTG CCCCTCTCTTATTGGGTAGCAGACTGGCTGTGTCTGCTTATCCCGCATGGTGGCACATGGCTGCCCAGAGCTCCC CAAAT AAC CT GT TAG GT T T C CAC C CACAGGGAGAAT CAGGCAGC C C GCT T GCT T AT T GT T T T T AAT AT ACT T T T C CAAACTACACAGACATTCCCAAAGCGGGTCTCCTTCTACCCAAAAGAGAAACGCTGGGCCTTACTAATTAACTGA AGACTCTGCTAGCTCGAGCCTTCCAAAACTCCATGCCACAATTGTTCAAACCATTTTCCAGAATACATCTTTTAA AATAACTTTTAGAAAATTGAACAAAGGGATTCATGTCTCAGCTTTATAGTCAAACCATGATCTTTTCTGAGGGTA TAGCCCATTTGGAGTTCCTGCTTAATCCCCTGATTAAAAACTGAATGGGGCTGAGTGCAGTGGCTCATGCCTATA T T C C CAGCACT T T GGGAGACAGAGGCAGGAGAAT T ACT T AAGGT CAGGAGT T T AAGAC CAT C CT GAGCAACAT AA CAAGTCCCCATCTCTAAGACAAAAAAAAAAGAACTGAGTGACATCTCACATCTCACATTTCTGAACATTAAACCC AGC CT T GAT AGC CAAAGAT GCT C GC CACT GAAGGAT C CAGGT AGT AT T GAGGGT T CT GT GGGGAT TAT C CAAAGA GAACTTTCTACAAAGTTTTAGGTGATGGCGATGCTAAAAGAAATGCTAAGAATTTCTCTCTTATATTAAAGAGAA CTATGGTCCTCTCATAAAATGTACCATTTATCACCAAATTTATCTCATAACCTAAGAGCTACCACTTACAAATTT GAAGGGAAAAAT T ACT ACAT T GT AATACT CAAGC CAACACAAAGAAT C CT AT C C CAGT T T CT T GAGT GGAT GGGC AAGAATATGGGGAATTTATTATGCAGTAACCTTCATCTCTCTTCTATAGGTCAGGATTTAAGTTTACCTCAAAAA T GGAAGAT T T T AACAT GGAGAGT GACAGCT T T GAAGAT T T CT GGAAAGGT GAAGAT CT T AGT AAT T ACAGT TACA GCTCTACCCTGCCCCCTTTTCTACTAGATGCCGCCCCATGTGAACCAGAATCCCTGGAAATCAACAAGTATTTTG TGGTCATTATCTATGCCCTGGTATTCCTGCTGAGCCTGCTGGGAAACTCCCTCGTGATGCTGGTCATCTTATACA GCAGGGTCGGCCGCTCCGTCACTGATGTCTACCTGCTGAACCTAGCCTTGGCCGACCTACTCTTTGCCCTGACCT TGCCCATCTGGGCCGCCTCCAAGGTGAATGGCTGGATTTTTGGCACATTCCTGTGCAAGGTGGTCTCACTCCTGA AGGAAGTCAACTTCTATAGTGGCATCCTGCTACTGGCCTGCATCAGTGTGGACCGTTACCTGGCCATTGTCCATG CCACACGCACACTGACCCAGAAGCGCTACTTGGTCAAATTCATATGTCTCAGCATCTGGGGTCTGTCCTTGCTCC TGGCCCTGCCTGTCTTACTTTTCCGAAGGACCGTCTACTCATCCAATGTTAGCCCAGCCTGCTATGAGGACATGG GCAACAATACAGCAAACTGGCGGATGCTGTTACGGATCCTGCCCCAGTCCTTTGGCTTCATCGTGCCACTGCTGA TCATGCTGTTCTGCTACGGATTCACCCTGCGTACGCTGTTTAAGGCCCACATGGGGCAGAAGCACCGGGCCATGC GGGTCATCTTTGCTGTCGTCCTCATCTTCCTGCTCTGCTGGCTGCCCTACAACCTGGTCCTGCTGGCAGACACCC T CAT GAGGAC C CAGGT GAT C CAGGAGAC CT GT GAGC GC C GCAAT CACAT C GAC C GGGCT CT GGAT GC CAC C GAGA TTCTGGGCATCCTTCACAGCTGCCTCAACCCCCTCATCTACGCCTTCATTGGCCAGAAGTTTCGCCATGGACTCC TCAAGATTCTAGCTATACATGGCTTGATCAGCAAGGACTCCCTGCCCAAAGACAGCAGGCCTTCCTTTGTTGGCT CTTCTTCAGGGCACACTTCCACTACTCTCTAAGACCTCCTGCCTAAGTGCAGCCCCGTGGGGTTCCTCCCTTCTC TTCACAGTCACATTCCAAGCCTCATGTCCACTGGTTCTTCTTGGTCTCAGTGTCAATGCAGCCCCCATTGTGGTC ACAGGAAGTAGAGGAGGCCACGTTCTTACTAGTTTCCCTTGCATGGTTTAGAAAGCTTGCCCTGGTGCCTCACCC CTTGCCATAATTACTATGTCATTTGCTGGAGCTCTGCCCATCCTGCCCCTGAGCCCATGGCACTCTATGTTCTAA GAAGT GAAAAT CTACACT CCAGT GAGACAGCT CT GCATACT CATTAGGAT GGCTAGTAT CAAAAGAAAGAAAAT C AGGCTGGCCAACGGGGTGAAACCCTGTCTCTACTAAAAATACAAAAAAAAAAAAAAATTAGCCGGGCGTGGTGGT GAGTGCCTGTAATCACAGCTACTTGGGAGGCTGAGATGGGAGAATCACTTGAACCCGGGAGGCAGAGGTTGCAGT GAGCCGAGATTGTGCCCCTGCACTCCAGCCTGAGCGACAGTGAGACTCTGTCTCAGTCCATGAAGATGTAGAGGA GAAACTGGAACTCTCGAGCGTTGCTGGGGGGGATTGTAAAATGGTGTGACCACTGCAGAAGACAGTATGGCAGCT T T C C T C AAAAC T T C AGAC AT AGAAT T AAC AC AT GAT C C T GCAAT T C C AC T T AT AGGAAT T GAC C C AC AAGAAAT G AAAGCAGGGACT T GAAC C CAT AT T T GT ACAC CAAT AT T CAT AGCAGCT T AT T CACAAGAC C CAAAAGGCAGAAGC AAC C CAAAT GT T CAT CAAT GAAT GAAT GAAT GGCT AAGCAAAAT GT GAT AT GT AC CT AAC GAAGT AT C CT T CAGC CTGAAAGAGGAATGAAGTACTCATACATGTTACAACACGGACGAACCTTGAAAACTTTATGCTAAGTGAAATAAG C C AGAC AT C AAC AGAT AAAT AGT T T AT GAT T C C AC C TAG AT GAGGT AC T GAGAGT GAAC AAAT T T AC AGAGAC AG AAAGCAGAACAGT GAT TAG CAGGGACT GAGGGGAGGGGAGCAT GGGAAGT GAC GGT T T AAT GGGCACAGGGT T TA T GT T T AGGAT GT T GAAAAAGT T CT GCAGAT AAACAGT AGT GAT AGT T GT AC C GCAAT GT GACT T AAT GC CACT AA AT T GAC AC T T AAAAAT GGT T T AAAT GGT CAAT T T T GT TAT GT AT AT T T TAT AT CAAT T T AAAAAAAAAC C T GAGC C C CAAAAGGT AT T T T AAT CAC CAAGGCT GAT T AAAC CAAGGCT AGAAC CAC CT GC CT AT AT T T T T T GT T AAAT GA TTTCATTCAATATCTTTTTTTTAATAAACCATTTTTACTTGGGTGTTTA

[0322] SEQ ID NO: 5 (CXCR2 mRNA sequence, NM_ 001168298.2): agtggtgata gctgagaata tgcagccgtt ttctccttcc tgggtacagt gctattctgc 61 ctagagctct gactaccacc caaccttgag gcacagtgaa gacatcggtg gccactccaa121 taacagcagg tcacagctgc tcttctggag gtgtcctaca ggtgaaaagc ccagcgaccc 181 agtcaggatt taagtttacc tcaaaaatgg aagattttaa catggagagt gacagctttg 241 aagatttctg gaaaggtgaa gatcttagta attacagtta cagctctacc ctgccccctt 301 ttctactaga tgccgcccca tgtgaaccag aatccctgga aatcaacaag tattttgtgg 361 tcattatcta tgccctggta ttcctgctga gcctgctggg aaactccctc gtgatgctgg 421 tcatcttata cagcagggtc ggccgctccg tcactgatgt ctacctgctg aacctagcct 481 tggccgacct actctttgcc ctgaccttgc ccatctgggc cgcctccaag gtgaatggct 541 ggatttttgg cacattcctg tgcaaggtgg tctcactcct gaaggaagtc aacttctata 601 gtggcatcct gctactggcc tgcatcagtg tggaccgtta cctggccatt gtccatgcca 661 cacgcacact gacccagaag cgctacttgg tcaaattcat atgtctcagc atctggggtc 721 tgtccttgct cctggccctg cctgtcttac ttttccgaag gaccgtctac tcatccaatg 781 ttagcccagc ctgctatgag gacatgggca acaatacagc aaactggcgg atgctgttac 841 ggatcctgcc ccagtccttt ggcttcatcg tgccactgct gatcatgctg ttctgctacg 901 gattcaccct gcgtacgctg tttaaggccc acatggggca gaagcaccgg gccatgcggg 961 tcatctttgc tgtcgtcctc atcttcctgc tctgctggct gccctacaac ctggtcctgc 1021 tggcagacac cctcatgagg acccaggtga tccaggagac ctgtgagcgc cgcaatcaca 1081 tcgaccgggc tctggatgcc accgagattc tgggcatcct tcacagctgc ctcaaccccc 1141 tcatctacgc cttcattggc cagaagtttc gccatggact cctcaagatt ctagctatac 1201 atggcttgat cagcaaggac tccctgccca aagacagcag gccttccttt gttggctctt 1261 cttcagggca cacttccact actctctaag acctcctgcc taagtgcagc cccgtggggt 1321 tcctcccttc tcttcacagt cacattccaa gcctcatgtc cactggttct tcttggtctc 1381 agtgtcaatg cagcccccat tgtggtcaca ggaagtagag gaggccacgt tcttactagt 1441 ttcccttgca tggtttagaa agcttgccct ggtgcctcac cccttgccat aattactatg 1501 tcatttgctg gagctctgcc catcctgccc ctgagcccat ggcactctat gttctaagaa 1561 gtgaaaatct acactccagt gagacagctc tgcatactca ttaggatggc tagtatcaaa 1621 agaaagaaaa tcaggctggc caacggggtg aaaccctgtc tctactaaaa atacaaaaaa 1681 aaaaaaaaat tagccgggcg tggtggtgag tgcctgtaat cacagctact tgggaggctg 1741 agatgggaga atcacttgaa cccgggaggc agaggttgca gtgagccgag attgtgcccc 1801 tgcactccag cctgagcgac agtgagactc tgtctcagtc catgaagatg tagaggagaa 1861 actggaactc tcgagcgttg ctggggggga ttgtaaaatg gtgtgaccac tgcagaagac 1921 agtatggcag ctttcctcaa aacttcagac atagaattaa cacatgatcc tgcaattcca 1981 cttataggaa ttgacccaca agaaatgaaa gcagggactt gaacccatat ttgtacacca 2041 atattcatag cagcttattc acaagaccca aaaggcagaa gcaacccaaa tgttcatcaa 2101 tgaatgaatg aatggctaag caaaatgtga tatgtaccta acgaagtatc cttcagcctg 2161 aaagaggaat gaagtactca tacatgttac aacacggacg aaccttgaaa actttatgct 2221 aagtgaaata agccagacat caacagataa atagtttatg attccaccta catgaggtac 2281 tgagagtgaa caaatttaca gagacagaaa gcagaacagt gattaccagg gactgagggg 2341 aggggagcat gggaagtgac ggtttaatgg gcacagggtt tatgtttagg atgttgaaaa 2401 agttctgcag ataaacagta gtgatagttg taccgcaatg tgacttaatg ccactaaatt 2461 gacacttaaa aatggtttaa atggtcaatt ttgttatgta tattttatat caatttaaaa 2521 aaaaacctga gccccaaaag gtattttaat caccaaggct gattaaacca aggctagaac 2581 cacctgccta tattttttgt taaatgattt cattcaatat ctttttttta ataaaccatt 2641 tttacttggg tgttta

[0323] SEQ ID NO: 6 (CXCR2 mRNA sequence, NM_ 001557.4): agagacagaa ggtggataga caaatctcca ccttcagact ggtaggctcc tccagaagcc 61 atcagacagg aagatgtgaa aatccccagc actcatccca gaatcactaa gtggcacctg 121 tcctgggcca aagtcccagg acagacctca ttgttcctct gtgggaatac ctccccagga 181 gggcatcctg gatttccccc ttgcaaccca ggtcagaagt ttcatcgtca aggttgtttc 241 atcttttttt tcctgtctaa cagctctgac taccacccaa ccttgaggca cagtgaagac 301 atcggtggcc actccaataa cagcaggtca cagctgctct tctggaggtg tcctacaggt 361 gaaaagccca gcgacccagt caggatttaa gtttacctca aaaatggaag attttaacat 421 ggagagtgac agctttgaag atttctggaa aggtgaagat cttagtaatt acagttacag 481 ctctaccctg cccccttttc tactagatgc cgccccatgt gaaccagaat ccctggaaat 541 caacaagtat tttgtggtca ttatctatgc cctggtattc ctgctgagcc tgctgggaaa 601 ctccctcgtg atgctggtca tcttatacag cagggtcggc cgctccgtca ctgatgtcta 661 cctgctgaac ctagccttgg ccgacctact ctttgccctg accttgccca tctgggccgc 721 ctccaaggtg aatggctgga tttttggcac attcctgtgc aaggtggtct cactcctgaa 781 ggaagtcaac ttctatagtg gcatcctgct actggcctgc atcagtgtgg accgttacct 841 ggccattgtc catgccacac gcacactgac ccagaagcgc tacttggtca aattcatatg901 tctcagcatc tggggtctgt ccttgctcct ggccctgcct gtcttacttt tccgaaggac 961 cgtctactca tccaatgtta gcccagcctg ctatgaggac atgggcaaca atacagcaaa 1021 ctggcggatg ctgttacgga tcctgcccca gtcctttggc ttcatcgtgc cactgctgat 1081 catgctgttc tgctacggat tcaccctgcg tacgctgttt aaggcccaca tggggcagaa 1141 gcaccgggcc atgcgggtca tctttgctgt cgtcctcatc ttcctgctct gctggctgcc 1201 ctacaacctg gtcctgctgg cagacaccct catgaggacc caggtgatcc aggagacctg 1261 tgagcgccgc aatcacatcg accgggctct ggatgccacc gagattctgg gcatccttca 1321 cagctgcctc aaccccctca tctacgcctt cattggccag aagtttcgcc atggactcct 1381 caagattcta gctatacatg gcttgatcag caaggactcc ctgcccaaag acagcaggcc 1441 ttcctttgtt ggctcttctt cagggcacac ttccactact ctctaagacc tcctgcctaa 1501 gtgcagcccc gtggggttcc tcccttctct tcacagtcac attccaagcc tcatgtccac 1561 tggttcttct tggtctcagt gtcaatgcag cccccattgt ggtcacagga agtagaggag 1621 gccacgttct tactagtttc ccttgcatgg tttagaaagc ttgccctggt gcctcacccc 1681 ttgccataat tactatgtca tttgctggag ctctgcccat cctgcccctg agcccatggc 1741 actctatgtt ctaagaagtg aaaatctaca ctccagtgag acagctctgc atactcatta 1801 ggatggctag tatcaaaaga aagaaaatca ggctggccaa cggggtgaaa ccctgtctct 1861 actaaaaata caaaaaaaaa aaaaaattag ccgggcgtgg tggtgagtgc ctgtaatcac 1921 agctacttgg gaggctgaga tgggagaatc acttgaaccc gggaggcaga ggttgcagtg 1981 agccgagatt gtgcccctgc actccagcct gagcgacagt gagactctgt ctcagtccat 2041 gaagatgtag aggagaaact ggaactctcg agcgttgctg ggggggattg taaaatggtg 2101 tgaccactgc agaagacagt atggcagctt tcctcaaaac ttcagacata gaattaacac 2161 atgatcctgc aattccactt ataggaattg acccacaaga aatgaaagca gggacttgaa 2221 cccatatttg tacaccaata ttcatagcag cttattcaca agacccaaaa ggcagaagca 2281 acccaaatgt tcatcaatga atgaatgaat ggctaagcaa aatgtgatat gtacctaacg 2341 aagtatcctt cagcctgaaa gaggaatgaa gtactcatac atgttacaac acggacgaac 2401 cttgaaaact ttatgctaag tgaaataagc cagacatcaa cagataaata gtttatgatt 2461 ccacctacat gaggtactga gagtgaacaa atttacagag acagaaagca gaacagtgat 2521 taccagggac tgaggggagg ggagcatggg aagtgacggt ttaatgggca cagggtttat 2581 gtttaggatg ttgaaaaagt tctgcagata aacagtagtg atagttgtac cgcaatgtga 2641 cttaatgcca ctaaattgac acttaaaaat ggtttaaatg gtcaattttg ttatgtatat 2701 tttatatcaa tttaaaaaaa aacctgagcc ccaaaaggta ttttaatcac caaggctgat 2761 taaaccaagg ctagaaccac ctgcctatat tttttgttaa atgatttcat tcaatatctt 2821 ttttttaata aaccattttt acttgggtgt tta

[0324] SEQ ID NO: 7 (CXCR2 protein sequence, NP_ 001 161770.1):1 MEDFNMESDS FEDFWKGEDL SNYSYSSTLP PFLLDAAPCE PESLE INKYF VVI IYALVFL61 LSLLGNSLVM LVI LYSRVGR SVTDVYLLNL ALADLLFALT LPIWAASKVN GWI FGTFLCK 121 VVSLLKEVNF YSGI LLLACI SVDRYLAIVH ATRTLTQKRY LVKFI CLS IW GLSLLLALPV 181 LLFRRTVYSS NVS PACYEDM GNNTANWRML LRI LPQS FGF IVPLLIMLFC YGFTLRTLFK 241 AHMGQKHRAM RVI FAVVLI F LLCWLPYNLV LLADTLMRTQ VIQETCERRN HIDRALDATE 301 I LGI LHSCLN PLIYAFI GQK FRHGLLKI LA IHGLI SKDSL PKDSRPS FVG SSSGHTSTTL

[0325] SEQ ID NO: 8 (CXCR2 protein sequence, NP_ 001548.1):1 MEDFNMESDS FEDFWKGEDL SNYSYSSTLP PFLLDAAPCE PESLE INKYFVVI IYALVFL61 LSLLGNSLVM LVI LYSRVGR SVTDVYLLNL ALADLLFALT LPIWAASKVN GWI FGTFLCK 121 VVSLLKEVNF YSGI LLLACI SVDRYLAIVH ATRTLTQKRY LVKFI CLS IW GLSLLLALPV 181 LLFRRTVYSS NVS PACYEDM GNNTANWRML LRI LPQS FGF IVPLLIMLFC YGFTLRTLFK 241 AHMGQKHRAM RVI FAVVLI F LLCWLPYNLV LLADTLMRTQ VIQETCERRN HIDRALDATE 301 I LGI LHSCLN PLIYAFI GQK FRHGLLKI LA IHGLI SKDSL PKDSRPS FVG SSSGHTSTTL

Claims

CLAIMS1. A method of preventing or reducing inflammation associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

2. The method of claim 1, wherein the female reproductive organs include ovaries, fallopian tubes, uterus, uterosacral ligament, the peritoneum, and the peritoneal fluid surrounding the pelvis.

3. The method of claim 1, wherein the inflammation is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

4. The method of claim 1, wherein the inflammation is not associated with cancer of the female reproductive organs.

5. The method of claim 4, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.

6. The method of claim 1, wherein the inflammation is not associated with an ovarian cyst or uterine fibroids.

7. The method of claim 3, wherein the inflammation is associated with endometriosis.

8. The method of claim 1, wherein the inflammation is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

9. The method of claim 1, wherein the IL-8 receptor inhibitor inhibits IL-8 receptor expression and / or activity.

10. The method of claim 9, wherein the IL-8 receptor inhibitor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to expression and / or activity prior to administration.

11. The method of claim 1, wherein the IL-8 receptor inhibitor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.

12. The method of claim 1, wherein the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2.

13. The method of claim 1, wherein the IL-8 receptor is CXCR1.

14. The method of claim 1, wherein the IL-8 receptor is CXCR2.

15. The method of claim 11, wherein the IL-8 receptor inhibitor is a small molecule inhibitor of IL-8 receptor.

16. The method of claim 15, wherein the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933.

17. The method of claim 16, wherein the small molecule inhibitor of IL-8 receptor is reparixin.

18. The method of claim 1, wherein the administering is systemic or local administration.

19. The method of claim 1, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having inflammation associated with female reproductive organs.

20. The method of claim 1, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having inflammation associated with female reproductive organs.

21. The method of claim 1, wherein the subject has been previously treated for inflammation associated with female reproductive organs.

22. The method of claim 1, wherein the subject has reoccurring inflammation associated with female reproductive organs.

23. The method of claim 1, wherein the subject has acute inflammation associated with female reproductive organs.

24. The method of claim 1, wherein the subject has chronic inflammation associated with female reproductive organs.

25. The method of claim 1, further comprising administering to a subject in need thereof a second therapeutic agent.

26. The method of claim 25, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), another analgesic, a hormonal agent, and surgical removal of a lesion(s).

27. The method of claim 1, wherein the subject is a mammal.

28. The method of claim 1, wherein the subject is human.

29. A method of preventing or reducing pain associated with female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

30. The method of claim 29, wherein the pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

31. The method of claim 29, wherein the pain is not associated with cancer of the female reproductive organs.

32. The method of claim 31, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.

33. The method of claim 29, wherein the pain is not associated with an ovarian cyst or uterine fibroids.

34. The method of claim 29, wherein the pain is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

35. The method of claim 29, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having pain associated with female reproductive organs.

36. The method of claim 29, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having pain associated with female reproductive organs.

37. The method of claim 29, wherein the subject has been previously treated for pain associated with female reproductive organs.

38. The method of claim 29, wherein the subject has reoccurring pain associated with female reproductive organs.

39. The method of claim 29, wherein the subject has acute pain associated with female reproductive organs.

40. The method of claim 29, wherein the subject has chronic pain associated with female reproductive organs.

41. The method of claim 29, wherein the subject has spontaneous pain associated with female reproductive organs.

42. The method of claim 29, wherein the subject has chronic and spontaneous pain associated with female reproductive organs.

43. The method of claim 29, further comprising administering to a subject a second therapeutic agent.

44. The method of claim 43, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of lesion(s).

45. A method of preventing or treating at least one lesion on female reproductive organs comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

46. The method of claim 45, wherein the at least one lesion is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.

47. The method of claim 45, wherein the at least one lesion is not associated with cancer of the female reproductive organs.

48. The method of claim 47, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.

49. The method of claim 45, wherein the at least one lesion is not associated with an ovarian cyst or uterine fibroids.

50. The method of claim 46, wherein the at least one lesion is associated with endometriosis.

51. The method of claim 45, wherein the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

52. The method of claim 45, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion on female reproductive organs.

53. The method of claim 45, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion on female reproductive organs.

54. The method of claim 45, wherein the subject has been previously treated for at least one lesion associated with female reproductive organs.

55. The method of claim 45, wherein the subject has reoccurring lesions associated with female reproductive organs.

56. The method of claim 45, wherein the subject has acute lesions associated with female reproductive organs.

57. The method of claim 45, wherein the subject has chronic lesions associated with female reproductive organs.

58. The method of claim 45, further comprising administering to a subject in need thereof a second therapeutic agent.

59. The method of claim 58, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of the at least one lesion.

60. A method of preventing or treating at least one lesion associated with endometriosis comprising administering an IL-8 receptor inhibitor to a subject in need thereof.

61. The method of claim 60, wherein the at least one lesion is present on or in any organ or tissue.

62. The method of claim 60, wherein the at least one lesion is present on the uterus, fallopian tubes, ovaries, intestines, rectum, bladder, uterosacral ligament, mesentery, peritoneum, liver, diaphragm, lungs, and / or surgical scar.

63. The method of claim 60, wherein the at least one lesion is not associated with cancer of the female reproductive organs.

64. The method of claim 63, wherein the cancer of the female reproductive organs includes uterine cancer or ovarian cancer.

65. The method of claim 60, wherein the at least one lesion is not associated with an ovarian cyst or uterine fibroids.

66. The method of claim 60, wherein the at least one lesion is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

67. The method of claim 60, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having at least one lesion associated with endometriosis.

68. The method of claim 60, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having at least one lesion associated with endometriosis.

69. The method of claim 60, wherein the subject has been previously treated for at least one lesion associated with endometriosis.

70. The method of claim 60, wherein the subject has reoccurring lesions associated with endometriosis.

71. The method of claim 60, wherein the subject has acute lesions associated with endometriosis.

72. The method of claim 60, wherein the subject has chronic lesions associated with endometriosis.

73. The method of claim 60, further comprising administering to a subject in need thereof a second therapeutic agent.

74. The method of claim 73, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of the lesions.

75. A composition comprising an agent that inhibits an IL-8 receptor.

76. The composition of claim 75, wherein the agent that inhibits IL-8 receptor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.

77. The composition of claim 75, wherein the agent that inhibits IL-8 receptor inhibits IL- 8 receptor expression and / or activity.

78. The composition of claim 77, wherein IL-8 receptor expression and / or activity is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or more as compared to an appropriate control.

79. The composition of claim 75, wherein the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2.

80. The composition of claim 75, wherein the IL-8 receptor is CXCR1.

81. The composition of claim 75, wherein the IL-8 receptor is CXCR2.

82. The composition of claim 75, wherein the agent that inhibits IL-8 receptor is a small molecule inhibitor of IL-8 receptor.

83. The composition of claim 82, wherein the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933.

84. The composition of claim 82, wherein the small molecule inhibitor of IL-8 receptor is reparixin.

85. The composition of claim 75, further comprising a pharmaceutically acceptable carrier.

86. The composition of claim 75, further comprising a second therapeutic agent.

87. The composition of claim 86, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of a lesion(s).

88. A method of treating or preventing inflammation, pain, or at least one lesion, the method comprising administering a composition of any of claims 60-72 to a subject in need thereof.

89. The method of claim 73, wherein the subject has or is at risk of having inflammation, pain, or lesions.

90. The method of claims 73 or 74, wherein the subject does not have cancer of the female reproductive organs.

91. The method of claims 73 or 74, wherein the subject does not have an ovarian cyst or uterine fibroids.

92. Use of the composition of any of claims 75-91 for the treatment or prevention of inflammation, pain or lesions.

93. A method of treating or preventing at least one lesion associated with endometriosis, the method comprising administering an IL-8 receptor inhibitor to a subject in need thereof, wherein the IL-8 receptor inhibitor is reparixin.

94. The method of claim 93, further comprising the step, prior to administering, diagnosing the subject of having or at risk of having endometriosis.

95. The method of claim 93, further comprising the step, prior to administering, receiving the results of an assay that diagnoses the subject of having or at risk of having endometriosis.

96. The method of claims 93-95, further comprising administering to a subject in need thereof, a second therapeutic agent.

97. The method of claim 96, wherein the second therapeutic agent is selected from a group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a hormonal agent, and surgical removal of a lesion(s).

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