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WO2025151629A2 - Méthodes et compositions pour traiter des maladies associées à une inflammation, une douleur et/ou des lésions - Google Patents

Méthodes et compositions pour traiter des maladies associées à une inflammation, une douleur et/ou des lésions

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Publication number
WO2025151629A2
WO2025151629A2 PCT/US2025/010932 US2025010932W WO2025151629A2 WO 2025151629 A2 WO2025151629 A2 WO 2025151629A2 US 2025010932 W US2025010932 W US 2025010932W WO 2025151629 A2 WO2025151629 A2 WO 2025151629A2
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WO
WIPO (PCT)
Prior art keywords
subject
female reproductive
reproductive organs
receptor
lesion
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Pending
Application number
PCT/US2025/010932
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WO2025151629A3 (fr
Inventor
Michael S. Rogers
Olivia HEINTZ
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Boston Childrens Hospital
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Boston Childrens Hospital
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Publication of WO2025151629A2 publication Critical patent/WO2025151629A2/fr
Publication of WO2025151629A3 publication Critical patent/WO2025151629A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • 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.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs 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.
  • 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.
  • the female reproductive organs include ovaries, fallopian tubes, uterus, uterosacral ligament, the peritoneum, and the peritoneal fluid surrounding the pelvis.
  • the inflammation is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.
  • the inflammation is not associated with cancer of the female reproductive organs.
  • the inflammation is not associated with an ovarian cyst or uterine fibroids.
  • the IL-8 receptor inhibitor inhibits IL-8 receptor expression and/or activity.
  • 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.
  • the administering is systemic or local administration.
  • the subject has reoccurring inflammation associated with female reproductive organs.
  • 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.
  • the pain is not associated with cancer of the female reproductive organs.
  • 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.
  • the subject has been previously treated for pain associated with female reproductive organs.
  • the subject has chronic pain associated with female reproductive organs.
  • the subject has chronic and spontaneous pain associated with female reproductive organs.
  • the subject has reoccurring lesions associated with female reproductive organs.
  • the subject has chronic lesions associated with female reproductive organs.
  • composition comprising an agent that inhibits an IL-8 receptor.
  • the agent that inhibits IL-8 receptor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.
  • the agent that inhibits IL-8 receptor inhibits IL-8 receptor expression and/or activity.
  • compositions further comprises a pharmaceutically acceptable carrier. In one embodiment of any aspect herein, the compositions further comprises a second therapeutic agent.
  • 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.
  • 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, the subject does not have an ovarian cyst or uterine fibroids.
  • compositions described herein for the treatment or prevention of inflammation, pain or lesions.
  • 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.
  • 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.
  • treatment also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).
  • 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).
  • agent described herein can be administered by any appropriate route which 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.
  • 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.
  • the subject is an experimental animal or animal substitute as a disease model.
  • 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).
  • “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.
  • “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.
  • 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
  • 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.
  • lesions of the female reproductive organs e.g., endometriosis
  • pain of the female reproductive organs e.g., endometriosis
  • increasing levels of inflammation of the female reproductive organs e.g., endometriosis
  • 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).
  • 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 limited to, 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.
  • 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.
  • 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.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, “individual,” “patient” and “subject” are used interchangeably herein.
  • 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.
  • 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.
  • a subject can also be one who has not been previously diagnosed as having such condition or related complications.
  • 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.
  • 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.
  • condition e.g., endometriosis
  • statically significant or “significantly” refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.
  • compositions, methods, and respective components thereof 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.
  • 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.
  • 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).
  • 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.
  • interleukin-8 receptor refers to an interleukin-8 receptor that is expressed on neutrophils.
  • IL-8 receptors can regulate 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.
  • IL-8 receptor A or CXCR1 and IL-8 receptor B or CXCR2. These names can be used interchangeably throughout the application.
  • 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.
  • CXCR2 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.
  • 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.
  • the female reproductive organs e.g., ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis
  • 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.
  • 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., the development 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.
  • pellet 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.
  • 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.
  • 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.
  • uterine 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.
  • 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.
  • 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.
  • 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.
  • spontaneous pain refers to pain that occurs suddenly and has no known stimulus or cause.
  • FIGs. 1A-1D show 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.
  • 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.
  • FIG. 3A-3C shows the effect of reparixin on endometriosis-induced spontaneous pain.
  • 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.
  • 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.
  • 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 of preventing 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.
  • 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.
  • the female reproductive organs include ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis.
  • the inflammation or pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.
  • the inflammation is associated with endometriosis.
  • 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.
  • the inflammation is not associated with an ovarian cyst or uterine fibroids.
  • inflammation 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.
  • pro-inflammatory signaling pathways and cytokines examples include TNF, IL-6, IL-1, and IL-8.
  • inflammation can occur upon activation of the IL-8 receptors CXCR1 and /or CXCR2.
  • 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.
  • the subject has reoccurring inflammation associated with female reproductive organs.
  • the subject has acute inflammation associated with female reproductive organs.
  • the subject has chronic inflammation associated with female reproductive organs.
  • 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.
  • 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
  • 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.
  • 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.
  • the subject has been previously treated for inflammation associated with female reproductive organs.
  • 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.
  • 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.
  • 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.
  • 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.
  • the female reproductive organs include ovaries, fallopian tubes, uterus, the tissue lining the pelvis, and the peritoneal fluid surrounding the pelvis.
  • the pain is associated with endometriosis, endometrioma, an ovarian remnant, pelvic pain syndrome, chronic pelvic inflammatory disease, or adenomyosis.
  • the pain is associated with endometriosis.
  • 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.
  • the pain is not associated with an ovarian cyst or uterine fibroids.
  • 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.
  • the subject has reoccurring pain associated with female reproductive organs.
  • the subject has chronic and spontaneous pain associated with female reproductive organs.
  • the at least one lesion is not associated with an ovarian cyst or uterine fibroids.
  • 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.
  • the subject has been previously treated for a lesion(s) associated with female reproductive organs.
  • the subject has reoccurring lesion associated with female reproductive organs. [00150] In one embodiment, the subject has acute lesion associated with female reproductive organs.
  • the subject has chronic lesion associated with female reproductive organs.
  • the subject has spontaneous lesion associated with female reproductive organs.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, ffenriti, 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).
  • 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.
  • 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).
  • Bacterial vaginosis 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 to Gardnerella 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.
  • the IL-8 receptor inhibitor is an antibody reagent, an inhibitory nucleic acid, or a small molecule.
  • the IL-8 receptor is selected from the group comprising CXCR1 and CXCR2.
  • 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.
  • 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.
  • 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.
  • CXCR1 referred to in this aspect, and all aspects and embodiments described herein in 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).
  • 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)
  • 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).
  • 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
  • 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: 1-2, SEQ ID NOs: 4-6.
  • 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.
  • 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
  • the nucleic acid inhibitor inhibits an IL-8 receptor (e.g., CXCR1 and CXCR2).
  • 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.
  • 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.
  • 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.
  • RNA strand the antisense strand
  • the use of these iRNAs enables the targeted degradation of mRNA transcripts, resulting in decreased expression and/or activity of the target.
  • RNA 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.
  • RISC RNA-induced silencing complex
  • an iRNA as described herein effects inhibition of the expression and/or activity of a target, e.g., CXCR1 and/or CXCR2.
  • contacting a cell with the inhibitor 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.
  • the inhibitor e.g., an iRNA
  • administering an inhibitor 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.
  • an inhibitor e.g., an iRNA
  • 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 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.
  • 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.
  • the region of complementarity 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.
  • 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.
  • the targeted region of an RNA targeted for cleavage will most often be part of a larger RNA molecule, often an mRNA molecule.
  • 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.
  • 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.
  • siRNA, shRNA, miRNA, and/or amiRNA 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).
  • the inhibitory nucleic acid is a guide nucleic acid (gNA).
  • gNA guide nucleic acid
  • 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.
  • an enzyme e.g., a nuclease
  • 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).
  • 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 is inserted into the site, although some nucleic acid material may be lost, resulting in a deletion.
  • 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.
  • 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.
  • the guide RNA comprises two short, non-coding RNA species referred to as CRISPR RNA (“crRNA”) and trans-acting RNA (“tracrRNA”).
  • 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.
  • PAM protospacer adjacent motif
  • nuclease complex induces cleavage of the target.
  • 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
  • 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).
  • the full-length guide nucleic acid strand can be any length.
  • 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.
  • a nucleic acid strand is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length.
  • the guide nucleic acid sequence is 10-30 nucleotides long.
  • 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.
  • such a chimeric gNA may be referred to as a single guide RNA (sgRNA).
  • the guide nucleic acid is designed using a guide design tool (e.g., BenchlingTM; Broad Institute GPPTM; CasOFFinderTM; CHOPCHOPTM; CRISPORTM; DeskgenTM; E-CRISPTM; GeneiousTM; GenHubTM; GUIDESTM (e.g., for library design); Horizon DiscoveryTM; IDTTM; Off-SpotterTM; and SynthegoTM; which are available on the world wide web).
  • a guide design tool e.g., BenchlingTM; Broad Institute GPPTM; CasOFFinderTM; CHOPCHOPTM; CRISPORTM; DeskgenTM; E-CRISPTM; GeneiousTM; GenHubTM; GUIDESTM (e.g., for library design); Horizon DiscoveryTM; IDTTM; Off-SpotterTM; and SynthegoTM; which are available on the world wide web).
  • 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.
  • end modifications e.g., 5’ end modifications (phosphorylation, conjugation, inverted linkages, etc.) 3’ end modifications (conjugation, DNA nucleotides, inverted linkages, etc.
  • base modifications e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners
  • 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.
  • modified RNAs that do not have a phosphorus atom in their intemucleoside backbone can also be considered to be oligonucleosides.
  • the modified RNA will have a phosphorus atom in its internucleoside backbone.
  • 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'.
  • 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.
  • 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
  • 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)
  • 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).
  • PNA peptide nucleic acid
  • 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.
  • RNA of an iRNA can also be modified to include one or more locked nucleic acids (LNA).
  • LNA locked nucleic acids
  • 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).
  • 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.
  • 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.
  • 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.
  • 2'-dimethylaminooxyethoxy i.e., a O(CH2)2ON(CH3)2 group, also known as 2'-DMA0E, as described in examples herein below
  • 2'-dimethylaminoethoxyethoxy also known in the art as 2'-O- dimethylaminoethoxyethyl or 2'-DMAEOE
  • 2'-O— CH2— O— CH2— N(CH2)2 also described in examples herein below.
  • 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.
  • An inhibitory nucleic acid can also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions.
  • 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 -trifluor
  • 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.
  • 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.
  • 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.
  • 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., 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).
  • Antibodies that specifically bind IL-8 receptors 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.
  • the inhibitor of the IL-8 receptor i.e., CXCR1 or CXCR2
  • the inhibitor of the IL-8 receptor is an antibody or an antigen binding fragment thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)].
  • Antibody inhibitors of IL-8 receptors can include polyclonal and monoclonal antibodies and antigen-binding derivatives or fragments thereof.
  • the inhibitor is an anti-CXCRl antibody, anti-CXCR2 antibody, anti-IL-8 receptor antibody, or an antigen binding fragment thereof.
  • 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.
  • 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.
  • the inhibitor of the IL-8 receptors is a small molecule.
  • the small molecule inhibitor of IL-8 receptor is selected from the group comprising AZD5069, AZD8309, danirixin, ladarixin, navarixin, reparixin, and SB656933.
  • the small molecule inhibitor of IL-8 receptor is reparixin.
  • 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.
  • an IL-8 receptor i.e, CXCR1, CXCR2
  • 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.
  • 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.
  • the dosage ranges for the administration of an IL-8 receptor inhibitor 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 condition described 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.
  • 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.
  • 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).
  • 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.
  • efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g., reduced pain and/or lesions of, e.g., the female reproductive organs.
  • 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”).
  • 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).
  • 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.
  • 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.
  • 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.
  • composition comprising an agent that inhibits an IL-8 receptor.
  • composition of any preceding paragraph, wherein the IL-8 receptor is CXCR1.
  • composition of any preceding paragraph, wherein the agent that inhibits IL-8 receptor is a small molecule inhibitor of IL-8 receptor.
  • 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.
  • composition of any preceding paragraph, further comprising a pharmaceutically acceptable carrier comprising a pharmaceutically acceptable carrier.
  • composition of any preceding paragraph for the treatment or prevention of inflammation, pain or lesions.
  • Endometriosis is an inflammatory, estrogen dependent disease often characterized by pain and/or infertility.
  • immune-mediated inflammatory factors play an active role in the induction of pain.
  • Reparixin is a CXCR1 and CXCR2 inhibitor preventing their 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.
  • mice 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.
  • 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.
  • 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).
  • HBSS Hank's Balanced Salt Solution
  • 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.
  • 18G needle cat #305185 Thin wall, BD, Franklin Lakes, NJ, USA
  • One donor mouse was used for every two endometriosis mice.
  • Lesion size is expressed in millimeters (mm) calculated from the mean of two measurements (width and height).
  • 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.
  • SEQ ID NO: 1 CXCR1 genomic sequence, NG_011814.1 : 5032-9153:
  • SEQ ID NO: 2 (CXCR1 mRNA sequence, NM 000634.3): actctgatct ctgactgcag ctcctactgt tggacacacc tggccggtgc ttcagttaga
  • SEQ ID NO: 5 (CXCR2 mRNA sequence, NM_ 001168298.2): agtggtgata gctgagaata tgcagccgtt ttctccttcc tgggtacagt gctattctgc 61 ctagagctct gactaccacc caaccttgag gcacagtgaa gacatcggtg gccactccaa 121 taacagcagg tcacagctgc tctggag gtgtcctaca ggtgaaaagc ccagcgaccc 181 agtcaggatt taagtttacc tcaaaaatgg aagattttaa catggagagt gacagctttg 241 aagatttctg gaaaggtg
  • 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 ctcccagga 181 gggcatcctg gatttccccc ttgcaaccca ggtcagaagt ttcatcgtca aggtttttc 241 atcttttttttttaa cagctctgac 241 atcttttttttt
  • SEQ ID NO: 7 CXCR2 protein sequence, NP_ 001 161770.1
  • SEQ ID NO: 8 CXCR2 protein sequence, NP_ 001548.1

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Abstract

La technologie ici décrite concerne des méthodes d'administration d'un inhibiteur du récepteur de l'IL-8 pour prévenir, réduire ou traiter une inflammation, une douleur et/ou des lésions. L'invention concerne également des compositions comprenant un inhibiteur du récepteur de l'IL-8.
PCT/US2025/010932 2024-01-10 2025-01-09 Méthodes et compositions pour traiter des maladies associées à une inflammation, une douleur et/ou des lésions Pending WO2025151629A2 (fr)

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