Methods of treating inflammatory conditions

Abstract

Provided herein are methods for treating inflammatory conditions of a pelvic organ and associated pain, with or without prior surgical removal of one or more inflammatory pelvic condition lesions, are disclosed. The methods include administering an anti-VEGF agent (e.g., Ranibizumab) into the target region and, optionally, administering of botulinum toxin A into the nerves innervating the target region in a subject.

Description

[0001] Attorney Docket No. 69831-701601

[0002] METHODS OF TREATING INFLAMMATORY CONDITIONS

[0003] CROSS-REFERENCE

[0004]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 763,788 filed February 26, 2025. The contents of the above-referenced applications are incorporated by reference in their entirety.

[0005] BACKGROUND

[0006]

[0002] Inflammatory conditions of pelvic organs, such as endometriosis, interstitial cystitis, and Asherman’s syndrome, are a collection of inflammatory conditions primarily affecting the female population of reproductive age and are characterized by symptoms including chronic inflammation, chronic pain, painful menstrual cramps (dysmenorrhea), infertility, painful intercourse (dyspareunia), scar tissue formation and painful urination (dysuria). These conditions can produce inflamed, fibrotic lesions or adhesions that may involve pelvic structures such as the peritoneum, ovaries, uterus, rectovaginal septum, bladder wall, and vaginal wall, depending on the underlying disease. Laparoscopic surgery is the mainstay of treatment for lesion removal if they manifest within the body cavity. While some lesions may be superficial, some conditions (such as in deeply invasive endometriosis (DIE)) manifest deeper infiltrating lesions which are more difficult to remove and may carry more risk to the patient if the lesion is capable of infiltrative spread.

[0007] SUMMARY

[0008]

[0003] Inflammatory conditions of a pelvic organ, like endometriosis, are commonly associated with painful symptoms that greatly affect quality of life. Lesions manifesting on reproductive organs or other sites within the pelvic region as a result of these conditions can be difficult to manage. Some will recur many times over a patient’s life, and some are un-removable due to their location and / or depth of penetration into surrounding tissues.

[0009]

[0004] In some aspects, provided herein are methods of treating an inflammatory condition of a pelvic organ in a subject. In some embodiments, the method may comprise administering an anti -vascular endothelial growth factor (anti-VEGF) agent to a target region in the pelvic organ. In some embodiments, the target region may comprise one or more lesions or scar tissue.

[0010]

[0005] In some embodiments, the subject may be a human subject. In some embodiments, the human subject may be post-menopausal. In some embodiments, the human subject may be menopausal. In some embodiments, the human subject may be of a reproductive age. In some embodiments, the target region may be a female reproductive organ and / or female genitalia. In some embodiments, the pelvic organ may be selected from a group consisting of: uterus, peritoneal cavity, rectovaginal area, bladder wall, bladder mucosa, vaginal interior, vaginal exterior, anus, ovary, and fallopian tube.

[0011]

[0006] In some embodiments, the target region may comprise scar tissue caused by the one or more lesions. In some embodiments, the scar tissue may be a wound bed remaining after a surgical removal ofAtorney Docket No. 69831-701601

[0012] one or more lesions from the target region. In some embodiments, the target region may comprise one or more lesions.

[0013]

[0007] In some embodiments, the target region may comprise two lesions. In some embodiments, each lesion may be at most about 5cm2in size. In some embodiments, each lesion may be about 5cm2, about 4cm2, about 3cm2, about 2cm2, or about 1cm2in size.

[0014]

[0008] In some embodiments, the inflammatory condition of a pelvic organ may be selected from the group consisting of: endometriosis, fibroids, pelvic inflammatory disease (PID), endometritis, interstitial cystitis, intrauterine adhesions (Asherman’s syndrome) and inflammatory myofibroblastic tumors (IMTs). In some embodiments, the treating of an inflammatory condition of a pelvic organ may comprise a reduction in one or more symptoms experienced by the human subject, wherein the one or more symptoms are selected from the group consisting of pain, redness, swelling, inflammation, and itchiness.

[0015]

[0009] In some embodiments, the anti-VEGF agent may be selected from: small molecules, proteins, oligonucleotides, and peptides. In some embodiments, the anti-VEGF agent may be a protein. In some embodiments, the protein may be an antibody or antigen-binding portion thereof. In some embodiments, the antibody may be a monoclonal antibody. In some embodiments, the antibody may be bevacizumab or antigen-binding portion thereof, or an agent with a clinical efficacy or function comparable to bevacizumab. In some embodiments, the antibody may be ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab. In some embodiments, the administering of the anti-VEGF agent may comprise injecting one or more doses of the anti-VEGF agent to the target region. In some embodiments, the method may further comprise administering (e.g., by injection) more than one dose of the anti-VEGF agent per lesion. In some embodiments, one dose of the anti-VEGF agent may be at least 0.1 mg per cm2of the target region. In some embodiments, the one dose of the anti-VEGF agent may be at most 5 mg per cm2of the target region. In some embodiments, one dose of the anti-VEGF agent may be from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region. In some embodiments, a total dose of the anti-VEGF agent administered may be at most 50mg.

[0016]

[0010] In some embodiments, the anti-VEGF agent may be isolated from an organism. In some embodiments, the anti-VEGF agent may be produced using recombinant expression of the anti-VEGF agent in the organism.

[0017] [OH] In some embodiments, the method further may comprise surgical removal of the one more lesions from the target region. In some embodiments, the one or more lesions may be performed prior to the administering of the anti-VEGF agent. In some embodiments, the one or more lesions may be performed concurrently with the administering of the anti-VEGF agent. In some embodiments, the surgical removal of the one or more lesions may be performed after the administering of the anti-VEGF agent.

[0018]

[0012] In some embodiments, the surgical removal may be performed with minimally invasive surgery. In some embodiments, the minimally invasive surgery may be robotic surgery. In some embodiments, the minimally invasive surgery may be laparoscopic surgery. In some embodiments, the lesions are removed partially based on photograph visualization. In some embodiments, the method further may comprise administering one or more pain relief medications to the human subject. In some embodiments, the one orAttorney Docket No. 69831-701601

[0019] more pain relief medication may be oral pain relief medication. In some embodiments, the oral pain relief medications are selected from analgesics, NSAIDs and opioids. In some embodiments, the method further may comprise administering agents capable of reducing scar tissue adhesion. In some embodiments, administering of the anti-VEGF agent to the target region may be localized administration via syringe injection.

[0020]

[0013] In some embodiments, the anti-VEGF agent may be directed within the one or more lesions. In some embodiments, the administering of the anti-VEGF agent may be directed within the wound bed remaining post-surgical removal of the one or more lesions from the target region. In some embodiments, the administering of the anti-VEGF agent may be directed to the periphery of the one or more lesions. In some embodiments, the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 10% as compared to a size of the lesion before the administration. In some embodiments, the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 15%, 20%, 25%, 30%, 40% 50%, 60%, 70%, or 80% as compared to a size of the lesion before the administration. In some embodiments, the administration of anti-VEGF agent results in a reduction in the number of the one or more lesions present in the target region before treatment.

[0021]

[0014] In some embodiments, the method further may comprise administering one or more doses of botulinum toxin A. In some embodiments, the one or more doses of botulinum toxin A may be administered to pelvic nerves innervating the target region. In some embodiments, the botulinum toxin A may be isolated from an organism. In some embodiments, the botulinum toxin A may be produced using recombinant expression of the botulinum toxin A in the organism. In some embodiments, the botulinum toxin A may be selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

[0022] INCORPORATION BY REFERENCE

[0023]

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025]

[0016] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0026]

[0017] FIGURE 1 is an illustration showing an inflammatory lesion (center) with halo-like mapping of localized anti-VEGF injections around the lesion margin, administered via dual- and quad-port multiport needles.Attorney Docket No. 69831-701601

[0027]

[0018] FIGURE 2 depicts histology images of an ex vzvo-cultured control endometriosis lesion. FIG. 2A depicts hematoxylin and eosin (H&E) staining of the endometriosis tissue while FIG. 2B depicts intense anti-CD31 labeling of the endometrial tissue, identifying endothelial cells and vasculature.

[0028]

[0019] FIGURE 3 depicts a magnified histology image of the endometriosis lesion tissue with intense anti-CD31 labeling identifying endothelial cells and vasculature.

[0029]

[0020] FIGURE 4 illustrates exemplary histology images of an endometriosis lesion cultured ex vivo after localized treatment with an anti-VEGF agent. FIG. 4A depicts a lower magnification image of treated endometriosis lesion displaying minimal anti-CD31 labeling while FIG.4B depicts a higher magnification image of treated endometrial tissue displaying minimal anti-CD31 labeling and small vascular lumen.

[0030]

[0021] FIGURE 5 illustrates exemplary histology images comparing an ex vzvo-cultured control endometriosis lesion (FIG. 5A) versus ex vzvo-cultured localized anti-VEGF- treated endometriosis lesion (FIG. 5B). FIG. 5A depicts control tissue with a thickened architecture and intense CD31 labeling, while FIG. 5B depicts treated tissue with reduced thickness and reduced CD31 labeling.

[0031]

[0022] FIGURE 6 illustrates exemplary histology images of an ex vzvo-cultured control endometriosis lesion (FIG. 6A) versus an ex vzvo-cultured localized anti-VEGF- treated endometriosis lesion (FIG. 6B). FIG. 6A depicts H&E staining of control endometriosis lesion tissue with high vascularity and thickness while FIG. 6B depicts H&E staining of treated endometriosis tissue, showcasing distinct tissue organization patterns.

[0032]

[0023] FIGURE 7 illustrates exemplary histology images of an ex vzvo-cultured control endometriosis lesion (FIG. 7A) an ex vzvo-cultured localized anti-VEGF- treated endometriosis lesion (FIG. 7B). FIG 7A depicts H&E staining of control tissue while FIG. 7B depicts H&E staining of treated endometrial tissue, showcasing vasculature differences.

[0033] DETAILED DESCRIPTION

[0034]

[0024] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0035]

[0025] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0036]

[0026] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0037]

[0027] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.Atorney Docket No. 69831-701601

[0038]

[0028] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0039]

[0029] I. DEFINITIONS

[0040]

[0030] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0041]

[0031] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0042]

[0032] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.

[0043]

[0033] The term “subject” encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is an adult human female. In some embodiments, the subject is a post-menopausal adult human female.

[0044]

[0034] The term “lesion(s)” encompasses an area of inflamed, abnormal or damaged tissue caused by injury, infection, or disease. Examples of lesions include wounds, ulcers, abscesses, sores, cysts, and tumors. In some embodiments, a lesion may be benign cell growth (i.e., not cancerous). A lesion may be caused by an infection (e.g., via pathogens such as bacterial or viruses). In some embodiments, a lesion may have non-pathogenic causes. In some cases, one or more lesions to be treated using the methods described herein are lesions in one or more pelvic organs.

[0045]

[0035] II. METHODS

[0046]

[0036] In some aspects of the present disclosure, described herein are methods of treating or preventing recurrence of an inflammatory condition of a pelvic organ in a subject. In some embodiments, the methods described herein are for treating an inflammatory condition of a pelvic organ in a subject. In some embodiments, the methods described herein are for preventing recurrence of an inflammatory condition of a pelvic organ in a human subject. In some embodiments, the human subject described herein comprises one or more lesions on or within a target region. In some embodiments, the method comprises administering an anti-vascular endothelial growth factor (VEGF) agent to the target region of a pelvic organ. In someAtorney Docket No. 69831-701601

[0047] embodiments, the method comprises administering botulinum toxin A to the target region of a pelvic organ. In some embodiments, the method comprises administering a combination of anti-VEGF agent and botulinum toxin A to the target region of a pelvic organ.

[0048] Subject

[0049]

[0037] In some embodiments, described herein are methods of treating a subject. In some embodiments, the subject is a human. In some embodiments, the subject is a human adult. In some embodiments, the subject is a human adult with female reproductive organs and / or genitalia (i.e., a vagina, a uterus, ovaries, and fallopian tubes). In some embodiments, the subject is of a human adult possessing female reproductive organs and / or genitalia and, who is of a reproductive age. In some embodiments, “reproductive age” comprises the period between the onset of menstruation (menarche) and the cessation of menstruation (menopause). In some embodiments, the subject is a menopausal human adult possessing female reproductive organs and / or genitalia. In some embodiments, the subject is a post-menopausal human adult possessing female reproductive organs and / or genitalia.

[0050]

[0038] In some embodiments, the subject may have a history of chronic pain, a history of opioid use to treat pain, or a combination thereof. In some embodiments, the subject may have a history of chronic pain. In some embodiments, the subject may have a history of opioid use to treat pain. In some embodiments, the subject may not have a history of chronic pain nor a history of opioid use to treat pain.

[0051] Pelvic Organ

[0052]

[0039] In some embodiments, described herein are methods of treating a pelvic organ. In some embodiments, a pelvic organ refers to an organ located within the pelvic region, inside or outside of the body, including, without limitation, the uterus, ovaries, fallopian tubes, peritoneal cavity, bladder, vagina, anus, and bowel. The pelvic organ may be selected from the group consisting of: uterus, peritoneal cavity, rectovaginal area, bladder wall, bladder mucosa, vaginal interior, vaginal exterior, ovary, and fallopian tube. In some embodiments, the pelvic organ is the uterus. In some embodiments, the pelvic organ to be treated includes the undersurface of the diaphragm which extends into the abdominal cavity. In some embodiments, the pelvic organ is the peritoneal cavity. In some embodiments, the pelvic organ is the rectovaginal area. In some embodiments, the pelvic organ is the bladder. In some embodiments, the pelvic organ is the bladder wall, the pelvic organ is the bladder mucosa. In some embodiments, the pelvic organ is the vagina. In some embodiments, the pelvic organ is the vaginal interior. In some embodiments, the pelvic organ is the vagina exterior. In some embodiments, the pelvic organ is the anus. In some embodiments, the pelvic organ is the ovary. In some embodiments, the pelvic organ is the fallopian tube. In some embodiments, the methods described herein can be used for treating one pelvic organ (e.g., uterus alone). In some embodiments, the methods described herein can be used for treating more than one pelvic organ (e.g., uterus and bladder).

[0053] Inflammatory Condition of a Pelvic Organ

[0054]

[0040] In some embodiments, described herein are methods of treating or preventing recurrence of inflammatory condition(s) of a pelvic organ. In some embodiments, an inflammatory condition of a pelvic organ encompasses a grouping of inflammatory diseases and disorders involving the pelvic organs of aAtorney Docket No. 69831-701601

[0055] female subject. In some embodiments, subjects with the inflammatory condition(s) of a pelvic organ commonly experience a chronic inflammatory response, redness, bleeding and / or fibrosis, and lower abdominal / pelvic pain. In some embodiments, an inflammatory condition of a pelvic organ in a subject described herein includes, but is not limited to endometriosis, endometritis, pelvic inflammatory disease (PID), inflammatory myofibroblastic tumors (IMTs), intrauterine adhesions (IUA / Asherman’s syndrome), Lichen sclerosus, interstitial cystitis, and fibroids. In some embodiments, the inflammatory condition of a pelvic organ is endometriosis, wherein the endometriosis is characterized as “deeply invasive endometriosis” (DIE). In some embodiments, the method further comprises administering anti-VEGF agents to the target region around DIE lesions, wherein the DIE lesion has penetrated deeper than 5 mm under the peritoneum.

[0056]

[0041] In some cases, the inflammatory condition can be a recurrence of a previous inflammatory condition on a different pelvic organ after removal of a first pelvic organ. For example, the subject with the inflammatory conditions may have undergone a hysterectomy to treat an inflammatory condition of a pelvic organ (i.e., endometriosis) and later developed recurrence of the inflammatory condition on another pelvic organ. In some cases, the inflammatory condition of a pelvic organ can be a recurrence of a previous inflammatory condition of a pelvic organ after surgical removal of the one or more lesions. In some embodiments, the inflammatory condition of a pelvic organ is endometriosis. In some embodiments, the inflammatory condition of a pelvic organ is interstitial cystitis. In some embodiments, the inflammatory condition of a pelvic organ is Lichen sclerosus. In some embodiments, the inflammatory condition of a pelvic organ is intrauterine adhesions (IUA / Asherman’s syndrome).

[0057]

[0042] In some embodiments, the inflammatory condition of a pelvic organ manifests within the pelvic cavity. In some embodiments, the inflammatory condition of a pelvic organ manifests on the uterus, an ovary, fallopian tube, peritoneal cavity, bladder, and bowel. In some embodiments, the inflammatory condition of a pelvic organ manifests on the uterus. In some embodiments, the inflammatory condition of a pelvic organ manifests on an ovary. In some embodiments, the inflammatory condition of a pelvic organ manifests on a fallopian tube. In some embodiments, the inflammatory condition of a pelvic organ manifests on the peritoneal cavity. In some embodiments, the inflammatory condition of a pelvic organ manifests on the bladder.

[0058]

[0043] In some embodiments, the inflammatory condition of a pelvic organ manifests outside of the pelvic cavity. In some embodiments, the inflammatory condition of a pelvic organ manifests on the genitals. In some embodiments, the inflammatory condition of a pelvic organ manifests on the anus.

[0059]

[0044] In some embodiments, the inflammatory condition of a pelvic organ is caused by an infection. In some embodiments, the infection is caused by pathogenic microorganisms comprising bacteria, viruses, fungi, parasites, or a combination thereof. In some embodiments, the infection is caused by microorganisms comprising bacteria. In some embodiments, the infection is caused by microorganisms comprising viruses. In some embodiments, the infection is caused by microorganisms comprising fungi. In some embodiments, the infection is caused by microorganisms comprising parasites.Atorney Docket No. 69831-701601

[0060]

[0045] In some embodiments, the inflammatory condition of a pelvic organ is not caused by an infection.

[0061]

[0046] In some embodiments, the inflammatory condition of a pelvic organ may be caused by neoplastic transformation. In some embodiments, the neoplastic transformation is cancerous (i.e., malignant). In some embodiments, the neoplastic transformation is non-cancerous (i.e., “benign”).

[0062]

[0047] In some embodiments, the subjects experience one or more of the following symptoms: chronic or intermitent pelvic pain, painful menstruation (dysmenorrhea), infertility, painful intercourse (dyspareunia) painful urination (dysuria), heavy menstruation, referred abdominal pain and cramping. In some embodiments, the subject described herein has one or more symptoms of the inflammatory conditions of a pelvic organ described herein. Examples of these symptoms in patients with endometriosis are also provided in: Shafrir, AL et al. (2018). Best Pract Res Clin Obstet Gynaecol, 51, 1-15, the content of which is incorporated herein.

[0063] Target Region

[0064]

[0048] In some embodiments, described herein are methods of treating a target region in a pelvic organ of the subject. In some embodiments, the target region may encompass the tissue which is affected by the one or more lesions or a region comprising scar tissue from a prior surgical intervention. In some embodiments, a target region of a subject described herein is on or within a pelvic organ. In some embodiments, the target region may be inside of the body. In some embodiments, the target region may be outside of the body. In some embodiments, the pelvic organ comprises a female reproductive organ and / or female genitalia, a non-reproductive organ, or a combination thereof. In some embodiments, the target region comprises the female reproductive organ and / or female genitalia. In some embodiments, the target region comprises the female reproductive organ. In some embodiments, the target region comprises the female genitalia. In some embodiments, the target region is on or within the uterus. In some embodiments, the target region is the exterior uterine lining. In some embodiments, the target region is the uterosacral ligaments. In some embodiments, the target region is on or within the pelvic peritoneal cavity. In some embodiments, the target region is on or within the rectovaginal area. In some embodiments, the target region is the anus. In some embodiments, the target region is on or within the vagina. In some embodiments, the target region is the vaginal interior. In some embodiments, the target region is the vaginal exterior. In some embodiments, the target region is on or within the bladder. In some embodiments, the target region is the bladder wall. In some embodiments, the target region is within the bladder mucosa. In some embodiments, the target region is on or within an ovary. In some embodiments, the target region is on or within a fallopian tube.

[0065]

[0049] In some embodiments, the target region may comprise more than one pelvic organ. In some embodiments, the target region may comprise a single lesion on or within a single pelvic organ. In some embodiments, the target region may comprise multiple lesions on or within a single pelvic organ. In some embodiments, the target region may comprise multiple lesions on or within multiple pelvic organs.

[0066]

[0050] In some embodiments, the target region comprises scar tissue or fibrotic tissue. In some embodiments the target region comprises scar tissue or fibrotic tissue caused by the one or more lesions. In some cases, scar tissue or fibrotic tissue may result from adhesions between pelvic organs created by the one or more lesions. In some cases, scar tissue or fibrotic tissue may result from the progression of a diseaseAttorney Docket No. 69831-701601

[0067] or condition. In some embodiments the target region comprises scar tissue or fibrotic tissue that forms as a symptom of a disease or condition. In some embodiments, the scar tissue or fibrotic tissue is located within the one or more lesions. In some embodiments, the scar tissue or fibrotic tissue is the wound bed remaining after a surgical removal of the one or more lesions from the target region. In some embodiments, the target region comprises the periphery of the one or more lesions.

[0068]

[0051] In some embodiments, an anti-VEGF agent may be administered to one or more lesions within the target region. In some cases, an anti-VEGF agent may be administered to one lesion within the target region. In some cases, an anti-VEGF agent may be administered to two lesions within the target region. In some cases, an anti-VEGF agent may be administered to three lesions within the target region. In some cases, an anti-VEGF agent may be administered to four lesions within the target region.

[0069]

[0052] In some embodiments, a lesion to be treated within the target region may be at most 6cm2in size. In some embodiments, a lesion to be treated within the target region may be at most 5cm2in size. In some embodiments, a lesion to be treated within the target region may be at most 4cm2in size. In some embodiments, a lesion to be treated within the target region may be at most 3cm2in size. In some embodiments, a lesion to be treated within the target region may be at most 2cm2in size. In some embodiments, a lesion to be treated within the target region may be at most 1cm2in size. In some embodiments, a lesion to be treated within the target region may be at least 0.5cm2in size. In some embodiments, a lesion to be treated within the target region may be at least 1cm2in size. The lesion size selected for treatment may differ in different conditions to be treated. For instance, in a subject with endometriosis, the lesion size to be treated may be at most 4cm2in size. In another instance, in a subject with interstitial cystitis or lichen sclerosus, the lesion size to be treated may be at most 2cm2in size. Surgical Removal

[0070]

[0053] In some embodiments, the method comprises surgical removal of the one or more lesions from the target region. In some embodiments, the surgical removal of the one or more lesions is performed before the administering of the anti-VEGF agent. In some embodiments, the surgical removal of the one or more lesions is performed before the administering of the anti-VEGF agent. In some embodiments, the surgical removal of the one or more lesions is performed before the administering of the botulinum toxin A. In some embodiments, the surgical removal of the one or more lesions is performed before the administering of the anti-VEGF agent and the botulinum toxin A. In some embodiments, the surgical removal is performed with open surgery. In some embodiments, the surgical removal is performed with minimally invasive surgery. In some embodiments, the type of minimally invasive surgery is selected from: Laparoscopy, Cystoscopy, Anoscopy, Enteroscopy, Hysteroscopy, Colonoscopy and Sigmoidoscopy. In some embodiments, the minimally invasive surgery is laparoscopic surgery. In some embodiments, the laparoscopic surgery comprises laser ablation, laser coagulation, mechanical curettage, or combinations thereof. In some embodiments, the laparoscopic surgery comprises a cutting water jet. In some embodiments, the laparoscopic surgery comprises a cutting waterjet followed by laser ablation, laser coagulation, mechanical curettage, or combinations thereof. In some embodiments, the laparoscopic surgery is robotic surgery. In some embodiments, the one or more lesions are invasive (e.g., DIE) and removed partially based onAttorney Docket No. 69831-701601

[0071] photograph visualization. In some embodiments, the one or more lesions are removed completely (e.g., superficial lesions) based on photograph visualization. Instances of surgical removal are also provided in: Duffy, JM et al. (2014). Cochrane Database Sy st Rev, 4, CC011031 the content of which is incorporated herein.

[0072]

[0054] In some embodiments, the one or more lesions do not require surgical removal from the target region. In these cases, the inflammatory condition of a pelvic organ may be treated with an anti-VEGF agent at a stage of disease early enough to not require surgical removal of the target region (i.e., clinical grades I-II out of IV). In some embodiments, the inflammatory condition of a pelvic organ may be treated with a botulinum toxin A at a stage of disease early enough to not require surgical removal of the target region (i.e., clinical grades I-II out of IV). In these cases, the inflammatory condition of a pelvic organ may be treated with an anti-VEGF agent and botulinum toxin A at a stage of disease early enough to not require surgical removal of the target region (i.e., clinical grades I-II out of IV).

[0073] Anti-VEGF Agents

[0074]

[0055] In some embodiments, an anti-VEGF agent described herein comprises an inhibitor of VEGF signaling. In some embodiments, the anti-VEGF agent disrupts the interaction between the VEGF protein (VEGF-A) and its receptors [VEGFR-1 (FLT-1) / VEGFR-2 (FLK1)]. In some cases, the anti-VEGF agent may reduce the translation, transcription, or function of the VEGF protein.

[0075]

[0056] The VEGF-A protein may have sequences, as non-limiting examples, as disclosed in the following: AAP86646.1 (Genbank, mRNA) and P15692.2 (Uniprot, Amino Acid). The VEGF protein may be one of many known isoforms, including but not limited to the following NCBI ref seqs: NP_003367.4, NP_001020537.2, NP_001020538.2, NP_001020539.2, NP_001020540.2, NP 001020541.2, NP_001028928.1, NP_001165093.1, NP_001165094.1, NP_001165095.1, NP 001165096.1, NP_001165097.1, NP_001165098.1, NP_001165099.1, NP_001165100.1, NP 001165101.1, NP_001191313. l, NP_001191314.1, NP_001273973.1, and NP_001303939.1.

[0076]

[0057] The VEGFR-1 protein may have sequences, as non-limiting examples, as disclosed in the following: CAA35946.1 (Genbank, mRNA) and P17948 (Uniprot, Amino Acid). The VEGFR-1 protein may be one of many known isoforms, including but not limited to the following NCBI ref seqs: NP_002010.2, NM_002019.4, NP_001153503.1, NM_001160031.1, NP_001153502.1, NM_001160030.1, NP_001153392.1, and NM_001159920.1.

[0077]

[0058] The VEGFR-2 protein may have sequences, as non-limiting examples, as disclosed in the following: AAC16450.1 (Genbank, mRNA) and P35968 (Uniprot, Amino Acid). The VEGFR-2 protein may be one of many known isoforms, including but not limited to the following NCBI ref seqs: NP_002244.1, and NM_002253.2.

[0078]

[0059] In some embodiments, the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

[0079]

[0060] In some embodiments, the anti-VEGF agent comprises a protein. In some embodiments, the protein is an antibody or antigen-binding portion thereof. In some embodiments, the protein is an antibody. In some embodiments, the antibody is a modified antibody. In some embodiments, the antibody is anAtorney Docket No. 69831-701601

[0080] immunoglobulin. In some embodiments, the immunoglobulin is an IgG. In some embodiments, the IgG is a modified IgG. In some embodiments, the modified IgG is glycosylated. In some embodiments, the modified IgG is aglycosylated. In some embodiments, the modified IgG contains either LALA or LALAPG Fc domain silencing mutations. In some embodiments, the modified IgG is humanized. In some embodiments, the IgG is monovalent. In some embodiments, the anti-VEGF agent is bevacizumab or an antigen-binding portion thereof, or another therapeutic agent with comparable clinical efficacy. In some embodiments, the agent is a formulation of bevacizumab. The formulation or clinical equivalent of bevacizumab are expected to have comparable clinical efficacy, stability and function as compared to bevacizumab.

[0081]

[0061] In some embodiments, the anti-VEGF agent is an antibody fragment. The antibody is selected from the group consisting of a light chain (VL), a heavy chain (VH), a single chain variable fragment (scFv), an F(ab')2 fragment, a Fab fragment, an Fd fragment, an Fv fragment, a nanobody (VHH or came lid) and a single domain antibody fragment (sdAb). In some embodiments, the anti-VEGF agent is ranibizumab, an antigen binding fragment thereof, or another therapeutic agent with comparable clinical efficacy. In some embodiments, the agent is a formulation of ranibizumab. The formulation or clinical equivalent of ranibizumab are expected to have comparable clinical efficacy, stability and function as compared to ranibizumab.

[0082]

[0062] In some embodiments, the anti-VEGF agent is a bivalent (2 targets) binding molecule, with at least one binding target specific to VEGF.

[0083]

[0063] In some embodiments, the anti-VEGF agent is a multivalent (3+ targets) binding molecule, with at least one binding target specific to VEGF.

[0084]

[0064] In some embodiments, the anti-VEGF agent is an extracellular protein degrader. In some embodiments, the anti-VEGF agent is an intracellular protein degrader.

[0085]

[0065] In some embodiments, the anti-VEGF agent is isolated from an organism. In some embodiments, the Anti-VEGF agent is produced using recombinant expression of the anti-VEGF agent in the organism. In some embodiments, the anti-VEGF agent is chemically synthesized.

[0086]

[0066] In some embodiments, the anti-VEGF agent is a receptor tyrosine kinase (RTK) inhibitor. In some embodiments, the RTK inhibitor is selected from: Type I inhibitors, Type II inhibitors, Type III inhibitors, Type IV inhibitors, and Type V inhibitors. For example, the RTK inhibitor could be Pazopanib, Sunitinib, or Sorafenib.

[0087]

[0067] In some embodiments, a subject may be administered an anti-VEGF agent as the only therapeutic agent. In some embodiments, a subject may be administered a combination of an anti-VEGF agent and botulinum toxin A.

[0088] Botulinum toxin A

[0089]

[0068] In some embodiments, a subject may be administered one or more doses of a botulinum toxin A.

[0090] In some embodiments, the botulinum toxin A comprises an inhibitor of acetylcholine from the presynaptic membranes of nerve terminals. The botulinum toxin A protein may have sequences, as non-limiting examples, as disclosed in the following: CAL82360.1 (Genbank, gDNA) and P0DPI1 (Uniprot, AminoAtorney Docket No. 69831-701601

[0091] Acid). In some embodiments, the botulinum toxin A may be administered for pain management. In some embodiments, the botulinum toxin A may be administered to supplement the anti-VEGF agent.

[0092]

[0069] In some embodiments, the botulinum toxin A described herein is isolated from an organism. In some embodiments, the botulinum toxin A is produced using recombinant expression of the botulinum toxin in the organism. In some embodiments, the botulinum toxin A is selected from: Onabotulinum toxin A (Botox), Abobotulinum toxin A (Dysport), Prabobotulinum toxin A (Jeuveau), Incobotulinum toxin A (Xeomin) and Daxibotulinum toxin A (Daxxify). In some embodiments, the botulinum toxin A is Onabotulinum toxin A (Botox).

[0093] Follow-Up Medications

[0094]

[0070] In some embodiments, the method further comprises administering one or more pain relief medications to the subject. In some embodiments, the pain relief medication is topical pain relief medication. In some embodiments, the topical pain relief medication comprises a cream, patch, bandage, dressing or combinations thereof.

[0095]

[0071] In some embodiments, the topical pain relief medication contains an active pain relief agent. In some embodiments, the topical pain relief medication delivers the active pain relief agent through the subject’s epithelial tissue. In some embodiments, the pain relief medication is oral pain relief medication. In some embodiments, the oral pain medications are selected from: analgesics, NSAIDs, and opioids.

[0096]

[0072] In some embodiments, the oral pain medication is an analgesic. In some embodiments, analgesic is Acetaminophen. In some embodiments, the oral pain medications are NSAIDs. In some embodiments, the NSAIDs comprise: Ibuprofen, Naproxen, Diclofenac, Celecoxib, Aspirin, Indomethacin, Meloxicam, or combinations thereof.

[0097]

[0073] In some embodiments, the oral pain medications comprise opioids. In some embodiments, the opioids comprise oxycodone, hydrocodone, and codeine. In some embodiments, the NSAIDs are given with opioids. In some embodiments, the NSAIDs are given in the absence of opioids. In some embodiments, the opioids are given in the absence of NSAIDs. In some embodiments, the one or more pain relief medications are administered prior to the anti-VEGF agent. In some embodiments, the one or more pain relief medications are administered prior to the botulinum toxin A. In some embodiments, the one or more pain relief medications are administered after the anti-VEGF agent. In some embodiments, the one or more pain relief medications are administered after the botulinum toxin A.

[0098]

[0074] In some embodiments, the anti-VEGF agent and / or botulinum toxin A are accompanied by one or more methods of reducing scar tissue adhesion. In some embodiments, the anti-VEGF agent and / or botulinum toxin A and pain relief medications are accompanied by one or more methods of reducing scar tissue adhesion. In some embodiments, the one or more methods of reducing scar tissue adhesion comprises: placement of expanded polytetroflourine materials, oxidized cellulose sheets, injectable sodium hyaluronate, methylcellulose, or a combination thereof. In some embodiments, the of reducing scar tissue adhesion comprises administering an injectable formulation of fluorouracil in the target region. In some embodiments, the of reducing scar tissue adhesion comprises administering an injectable formulation of triamcinolone in the target region. In some embodiments, the method comprises injecting equal volumesAtorney Docket No. 69831-701601

[0099] of fluorouracil and triamcinolone to reduce scar tissue adhesion. In some embodiments, the fluorouracil may be at a concentration from about 30mg / mL to about 70 mg / mL. In some embodiments, the fluorouracil may be at a concentration of about 50mg / mL. In some embodiments, the triamcinolone may be at a concentration from about lOmg / mL to about 30mg / mL. In some embodiments, the triamcinolone may be at a concentration of about 20mg / mL.

[0100] Anti-VEGF Administration

[0101]

[0075] In some embodiments, the method comprises administering an anti-vascular endothelial growth factor (anti-VEGF) agent to the target region in the pelvic organ.

[0102]

[0076] In some embodiments, the administering of the anti-VEGF agent comprises injecting one or more doses of the anti-VEGF agent to the target region. In some embodiments, the method comprises administering (e.g., by injection) more than one dose of the anti-VEGF agent. In some embodiments, at least one dose of the anti-VEGF agent may be administered. In some embodiments, two doses of the anti-VEGF agent may be administered. In some embodiments, three doses of the anti-VEGF agent may be administered. In some embodiments, four doses of the anti-VEGF agent may be administered. In some embodiments, five doses of the anti-VEGF agent may be administered.

[0103]

[0077] In some cases, a subject is administered one or more doses of an anti-VEGF agent. The total dose administered to a subject may be from about O.lmg to about 50mg. In some cases, the total dose is an amount of anti-VEGF agent administered to the subject in one day. In some cases, the total dose is an amount of anti-VEGF agent administered to the subject in more than one day. For instance, the total dose may be an amount of anti-VEGF agent administered to the subject over a course of 2 days. 3 days, 5 days, 1 week, 2 weeks, or 1 month. In some embodiments, a total dose of an anti-VEGF agent administered to a subject may be 0.1 mg to 50 mg. In some embodiments, a total dose of an anti-VEGF agent administered to a subject may be 0.1 mg to 0.25 mg, 0.1 mg to 1 mg, 0.1 mg to 5 mg, 0.1 mg to 10 mg, 0.1 mg to 20 mg, 0.1 mg to 30 mg, 0.1 mg to 40 mg, 0.1 mg to 50 mg, 0.25 mg to 1 mg, 0.25 mg to 5 mg, 0.25 mg to 10 mg, 0.25 mg to 20 mg, 0.25 mg to 30 mg, 0.25 mg to 40 mg, 0.25 mg to 50 mg, 1 mg to 5 mg, 1 mg to 10 mg, 1 mg to 20 mg, 1 mg to 30 mg, 1 mg to 40 mg, 1 mg to 50 mg, 5 mg to 10 mg, 5 mg to 20 mg, 5 mg to 30 mg, 5 mg to 40 mg, 5 mg to 50 mg, 10 mg to 20 mg, 10 mg to 30 mg, 10 mg to 40 mg, 10 mg to 50 mg, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 30 mg to 40 mg, 30 mg to 50 mg, or 40 mg to 50 mg. In some embodiments, a total dose of an anti-VEGF agent administered to a subject may be 0.1 mg, 0.25 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, a total dose of an anti-VEGF agent administered to a subject may be at least 0.1 mg, 0.25 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg. In some embodiments, a total dose of an anti-VEGF agent administered to a subject may be at most 0.25 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg.

[0104]

[0078] In some embodiments, a dose of the anti-VEGF agent administered to a subject in one day may be about 1 mg per cm2of the target region to about 40 mg per cm2of the target region. In some embodiments, a dose of the anti-VEGF agent administered in one day may be about 5 mg per cm2of the target region to about 35 mg per cm2of the target region. In some embodiments, a dose of the anti-VEGF agent administered in one day may be about 10 mg per cm2of the target region to about 25 mg per cm2of theAtorney Docket No. 69831-701601

[0105] target region. In some embodiments, a dose of the anti-VEGF agent administered in one day may be about 15 mg per cm2of the target region to about 20 mg per cm2of the target region.

[0106]

[0079] In some embodiments, two doses of the anti-VEGF agent may be administered on the same day. In some embodiments, three doses of the anti-VEGF agent may be administered on the same day. In some embodiments, four doses of the anti-VEGF agent may be administered on the same day. In some embodiments, five doses of the anti-VEGF agent may be administered on the same day.

[0107]

[0080] In some embodiments, the one or more doses of the anti-VEGF agent may be administered in a dosing regimen over days. A single dose may be administered for instance, prior to surgical removal of the one or more lesions. In some embodiments, the anti-VEGF agent may be administered within two weeks of the surgical removal. In one example, the anti-VEGF agent may be administered 2 weeks, 1 week, 5 days, 3 days, or 1 day before the surgical removal of one or more lesions. In another example, the anti-VEGF agent may be administered 1 day, 3 days, 5 days, 1 week, or 2 weeks after the surgical removal of one or more lesions. In yet another example, one or more doses of an anti-VEGF agent may be administered to the target region before surgical removal, and the surgical removal may then be followed one or more additional doses of the anti-VEGF agent. In some cases, such multiple doses of an anti-VEGF agent may be administered over a day, over 2 days, over 5 days or more than 5 days.

[0108]

[0081] In some embodiments, subjects to be treated using the methods described herein may have different stages or degrees of a disease or a condition. In some cases, a subject to be treated has an earlier or less severe degree of a disease or condition. In such a case, the subject may only present with shallow, superficial lesions with minimal or no scarring. In some cases, a subject to be treated has a mild or moderate degree of a disease or condition. In such a case, the subject may present with deep lesions with minor or dense adhesions. In some cases, a subject to be treated has a severe stage or degree of a disease or condition. In such a case, the subject may present with many deep lesions and significant adhesions (based on the size of the adhesion).

[0109]

[0082] In some embodiments, a subject is administered the one or more doses of the anti-VEGF agent after surgical removal of the one or more lesions. In some embodiments, a subject is administered the one or more doses of the anti-VEGF agent before developing a severe stage or degree of a disease or condition. For instance, a subject may be treated before they develop a severe form of the disease or condition, e.g., before developing deep lesions and / or significant adhesions. In another instance, a subject may be treated before they develop a moderate form of the disease or condition, e.g., before developing dense adhesions. In such cases, the treatment may prevent exacerbation or aggravation of the disease or condition in a subject. The treatment may also prevent recurrence of the disease or condition in the subject.

[0110]

[0083] In some embodiments, the one or more doses of the anti-VEGF agent may be administered at a time interval between one or more doses. In some embodiments, the time interval may be one day. In some embodiments, the time interval may be two days. In some embodiments, the time interval may be two weeks. In some embodiments, the time interval may be one month. In some embodiments, the time interval may be two months. In some embodiments, the time interval may be three months. In some embodiments,Atorney Docket No. 69831-701601

[0111] the time interval may be six months. In some embodiments, the time interval may be one year. In some embodiments, the time interval may be 3 years. In some embodiments, the time interval may be 5 years.

[0112]

[0084] In some embodiments, the administering of the anti-VEGF agent is via syringe injection. Localized (or local) administration may include applying a therapeutic agent directly to a specific intended site of action in the body in contrast to systemic (i.e., intravenous) administration which distributes the therapeutic agent to the entire body. In some embodiments, the administering of the anti-VEGF agent can be a localized administration. In some embodiments, the administering of the anti-VEGF agent is a systemic administration. In some embodiments, the administering of the anti-VEGF agent is localized administration of the anti-VEGF agent via syringe injection. In some embodiments, the administering of the anti-VEGF agent is guided to the pelvic organ.

[0113]

[0085] In some embodiments, a subject may be administered bevacizumab at a concentration of 0.25-5mg / mL per cm2of the target region to treat endometriosis. In some embodiments, a subject may be administered bevacizumab at a concentration of 0.5-2.5mg / mL per cm2of the target region to treat endometriosis. In some embodiments, a subject may be administered bevacizumab at a concentration of 1-1.5mg / mL per cm2of the target region to treat endometriosis.

[0114]

[0086] In some embodiments, a subject may be administered ranibizumab at a concentration of 0.25-5mg / mL per cm2of the target region to treat endometriosis. In some embodiments, a subject may be administered ranibizumab at a concentration of 0.5-2.5mg / mL per cm2of the target region to treat endometriosis. In some embodiments, a subject may be administered ranibizumab at a concentration of 1-1.5mg / mL per cm2of the target region to treat endometriosis.

[0115]

[0087] In some embodiments, a subject may be administered bevacizumab at a concentration of 5mg / mL per cm2of the target region to treat interstitial cystitis. In some embodiments, a subject may be administered bevacizumab at a concentration of 3.5mg / mL per cm2of the target region to treat interstitial cystitis. In some embodiments, a subject may be administered bevacizumab at a concentration of Img / mL per cm2of the target region to treat interstitial cystitis.

[0116]

[0088] In some embodiments, a subject may be administered ranibizumab at a concentration of 5mg / mL per cm2of the target region to treat interstitial cystitis. In some embodiments, a subject may be administered ranibizumab at a concentration of 3.5mg / mL per cm2of the target region to treat interstitial cystitis. In some embodiments, a subject may be administered ranibizumab at a concentration of Img / mL per cm2of the target region to treat interstitial cystitis.

[0117]

[0089] In some embodiments, a subj ect may be administered bevacizumab at a concentration of 3.5mg / mL per cm2of the target region to treat lichen sclerosus. In some embodiments, a subject may be administered bevacizumab at a concentration of 5mg / mL per cm2of the target region to treat lichen sclerosus. In some embodiments, a subject may be administered bevacizumab at a concentration of Img / mL per cm2of the target region to treat lichen sclerosus.

[0118]

[0090] In some embodiments, a subject may be administered ranibizumab at a concentration of 3.5mg / mL per cm2of the target region to treat lichen sclerosus. In some embodiments, a subject may be administered ranibizumab at a concentration of 5mg / mL per cm2of the target region to treat lichen sclerosus. In someAtorney Docket No. 69831-701601

[0119] embodiments, a subject may be administered ranibizumab at a concentration of Img / mL per cm2of the target region to treat lichen sclerosus.

[0120]

[0091] In some embodiments, one or more doses of a formulation of an anti-VEGF agent may be administered to a target region in the subject. In some cases, a formulation of an anti-VEGF agent, e.g., ranibizumab or bevacizumab, may be administered at a concentration from about 0.25mg / mL to about 5mg / mL per cm2of a target region in a subject. In such cases, a subject may receive from about 0.5mL to about 1.5mL of an anti-VEGF formulation. In one example, a subject receives ImL of an anti-VEGF formulation at a concentration from about 0.25mg / mL to about 5mg / mL per cm2of the target region. In another example, a subject receives 0.5mL of an anti-VEGF formulation at a concentration from about 0.25mg / mL to about 5mg / mL per cm2of the target region. In one example, a subject receives I.5mL of an anti-VEGF formulation at a concentration from about 0.25mg / mL to about 5mg / mL per cm2of the target region.

[0121]

[0092] In some embodiments, parameters of the target region (i.e., lesion number and / or size, specific pelvic organs involved, etc.) will influence the administered concentration of the anti-VEGF agent.

[0122]

[0093] In some embodiments, the administering of the anti-VEGF agent is directed to tissue within the target region. Depending on target region size, a subject may receive multiple administrations of the anti-VEGF agent to the target region until a desired cumulative dosage is reached. In some embodiments, the anti-VEGF agent is directed to the one or more lesions.

[0123] Botulinum Toxin A Administration

[0124]

[0094] In some embodiments, the method comprises administering botulinum toxin A to the target region in the pelvic organ.

[0125]

[0095] In some embodiments, the administering of the botulinum toxin A comprises injecting one or more doses of the botulinum toxin A to the target region. In some embodiments, more than one dose of the botulinum toxin A may be administered. In some embodiments, one dose of the botulinum toxin A may be administered. In some embodiments, two doses of the botulinum toxin A may be administered. In some embodiments, three doses of the botulinum toxin A may be administered. In some embodiments, four doses of the botulinum toxin A may be administered. In some embodiments, five doses of the botulinum toxin A may be administered.

[0126]

[0096] In some embodiments, a single dose of the botulinum toxin A may be about 5 U per cm2of the target region to about 30 U per cm2of the target region. In some embodiments, a single dose of the botulinum toxin A may be about 5 U per cm2of the target region to about 7 U per cm2of the target region, about 5 U per cm2of the target region to about 10 U per cm2of the target region, about 5 U per cm2of the target region to about 15 U per cm2of the target region, about 5 U per cm2of the target region to about 20 U per cm2of the target region, about 5 U per cm2of the target region to about 25 U per cm2of the target region, about 5 U per cm2of the target region to about 30 U per cm2of the target region, about 7 U per cm2of the target region to about 10 U per cm2of the target region, about 7 U per cm2of the target region to about 15 U per cm2of the target region, about 7 U per cm2of the target region to about 20 U per cm2of the target region, about 7 U per cm2of the target region to about 25 U per cm2of the target region, about 7 UAtorney Docket No. 69831-701601

[0127] per cm2of the target region to about 30 U per cm2of the target region, about 10 U per cm2of the target region to about 15 U per cm2of the target region, about 10 U per cm2of the target region to about 20 U per cm2of the target region, about 10 U per cm2of the target region to about 25 U per cm2of the target region, about 10 U per cm2of the target region to about 30 U per cm2of the target region, about 15 U per cm2of the target region to about 20 U per cm2of the target region, about 15 U per cm2of the target region to about 25 U per cm2of the target region, about 15 U per cm2of the target region to about 30 U per cm2of the target region, about 20 U per cm2of the target region to about 25 U per cm2of the target region, about 20 U per cm2of the target region to about 30 U per cm2of the target region, or about 25 U per cm2of the target region to about 30 U per cm2of the target region. In some embodiments, a single dose of the botulinum toxin A may be about 5 U per cm2of the target region, about 7 U per cm2of the target region, about 10 U per cm2of the target region, about 15 U per cm2of the target region, about 20 U per cm2of the target region, about 25 U per cm2of the target region, or about 30 U per cm2of the target region. In some embodiments, a single dose of the botulinum toxin A may be at least about 5 U per cm2of the target region, about 7 U per cm2of the target region, about 10 U per cm2of the target region, about 15 U per cm2of the target region, about 20 U per cm2of the target region, or about 25 U per cm2of the target region. In some embodiments, a single dose of the botulinum toxin A may be at most about 7 U per cm2of the target region, about 10 U per cm2of the target region, about 15 U per cm2of the target region, about 20 U per cm2of the target region, about 25 U per cm2of the target region, or about 30 U per cm2of the target region.

[0128]

[0097] In some embodiments, two doses of the botulinum toxin A may be administered on the same day. In some embodiments, three doses of the botulinum toxin A may be administered on the same day. In some embodiments, four doses of the botulinum toxin A may be administered on the same day. In some embodiments, five doses of the botulinum toxin A may be administered on the same day.

[0129]

[0098] In some embodiments, the one or more doses of the botulinum toxin A may be administered in a dosing regimen. A single dose may be administered for instance, prior to surgical removal of the one or more lesions. The surgical removal may then be followed by additional doses of the one or more doses. In some embodiments, a single dose may only be administered following surgical removal of the one or more lesions.

[0130]

[0099] In some embodiments, the administering of a botulinum toxin A to the target region is by injection. In some embodiments, the botulinum toxin A is administered in a formulation. In some embodiments, the administering of the botulinum toxin A formulation is administered at a depth of 4- 10mm. In some embodiments, the administering of the botulinum toxin A formulation is directed to sensory pelvic nerves within or surrounding the target region. The method may include other details described herein.

[0131]

[0100] In some embodiments, the botulinum toxin A formulation is Onabotulinum toxin A. In one instance, a subject may be administered an anti-VEGF agent and Onabotulinum toxin A. In such instances, a dose of Onabotulinum toxin A may be at least 5U / cm2of the target region. In such instances, a dose of Onabotulinum toxin A may be at most I0U / cm2of the target region. In some embodiments, the administering of the anti-VEGF agent and the Onabotulinum toxin A is directed to tissue within the target region, or to pelvic nerves innervating the target region. Depending on target region size, a subject mayAtorney Docket No. 69831-701601

[0132] receive multiple administrations of the Onabotulinum toxin A until a desired cumulative dosage is reached. Depending on target region size, a subject may receive multiple administrations of the anti-VEGF agent and the Onabotulinum toxin A until a desired cumulative dosage is reached.

[0133]

[0101] In some embodiments, the botulinum toxin A formulation is Incobotulinum toxin A. In one instance, a subject may be administered an anti-VEGF agent and Incobotulinum toxin A. In such instances, a dose of Incobotulinum toxin A may be at least 8U / cm2of the target region. In such instances, a dose of Incobotulinum toxin A may be at most 15U / cm2of the target region.

[0134]

[0102] In some embodiments, the botulinum toxin A formulation is Abobotulinum toxin A. In one instance, a subject may be administered an anti-VEGF agent and Abobotulinum toxin A. In such instances, a dose of Abobotulinum toxin A may be at least 15U / cm2of the target region. In such instances, a dose of Abobotulinum toxin A may be at most 30U / cm2of the target region.

[0135]

[0103] In some embodiments, botulinum toxin A formulation is Prabobotulinum toxin A. In one instance, a subject may be administered an anti-VEGF agent and Prabobotulinum toxin A. In such instances, a dose of Prabobotulinum toxin A may be at least 5U / cm2of the target region. In such instances, a dose Prabobotulinum toxin A may be at most I0U / cm2of the target region.

[0136]

[0104] In some embodiments, botulinum toxin A formulation comprises Daxibotulinum toxin A. In one instance, a subject may be administered an anti-VEGF agent and Daxibotulinum toxin A. In such instances, a dose of Daxibotulinum toxin A may be at least I0U / cm2of the target region. In such instances, a dose of Daxibotulinum toxin A may be at most 20U / cm2of the target region.

[0137] Syringe

[0138]

[0105] In some embodiments, the administering is performed by a syringe comprising one or more needles. In some embodiments, the one or more needles used for the administering of the anti-VEGF agents is a 25G - 34G needle. In some embodiments, the one or more needles comprises a multiport needle head able to penetrate I -3mm of tissue and deliver liquid in multiple directions from the needle center. In some embodiments, the multi-port needle head is a quad-port needle head able to penetrate I -3mm of tissue and deliver liquid in four directions from the needle center. In some embodiments, the multi-port needle head is a dual port needle head able to penetrate I -3mm of tissue and deliver liquid in two directions from the needle center. In some embodiments, the one or more needles comprises a catheter.

[0139]

[0106] In some embodiments, the administering of the anti-VEGF agent is performed with hollow insulated needles. In some embodiments, the hollow insulated needles are combined with radiofrequency pulses. In some embodiments, the radiofrequency pulses are at frequencies ranging from 400-800kHz. In some embodiments, the radiofrequency pulses have a duration ranging from I00ms-4sec. In some embodiments, the hollow insulated needles are combined with high voltage nanopulse electrical energy. In some embodiments, the hollow insulated needles are combined with radiofrequency pulses.

[0140]

[0107] In some embodiments, the administering of the anti-VEGF agent comprises a water jet beam solution. In some embodiments, the administering of the waterjet beam solution is followed by coagulation with KTP laser. In some embodiments, the waterjet beam solution is followed by suction to remove tissue. In some embodiments, the waterjet solution and suction are operated by a robotic arm.Atorney Docket No. 69831-701601

[0141]

[0108] In some embodiments, the robotic arm is employed with stereotaxic mapping to target endometrial tissue. In some embodiments, the stereotaxic mapping is followed by anti-VEGF agent infusion via water jet. In some embodiments, the anti-VEGF agent infusion via waterjet results in the formation of a reservoir within the tissue in the target region.

[0142] Outcomes

[0143]

[0109] In some embodiments, the method results in one or more positive treatment outcomes. In some embodiments, the one or more positive treatment outcomes may comprise: a flatening of the one or more lesions, a reduction in scar formation post-surgery, a reduction in number of the one or more lesions, a reduction in size of the one or more lesions, a reduction of one or more symptoms experienced by the subject, a prevention of vascular reappearance at the target region, a prevention of regrowth of the one or more lesions at the target region, or a combination thereof.

[0144] [HO] In some embodiments, the one or more positive treatment outcomes is the flatening of the one or more lesions. In some embodiments, the flatening of the one or more lesions comprises the flatening of the peritoneal lining comprising the one or more lesions. In some embodiments, the one or more lesions comprise endometriosis lesions.

[0145] [Hl] In some embodiments, the one or more positive treatment outcomes is the reduction in scar formation post-surgery. Scar formation can be evaluated using standardized means known in the art, such as the Hollander Scar Score. In some embodiments, scar formation is evaluated based on pigmentation, vascularity, pliability, height, palpability, or combinations thereof. In some embodiments, scar formation is evaluated based on pigmentation. In some embodiments, scar formation is evaluated based on pliability. In some embodiments, scar formation is evaluated based on vascularity. In some embodiments, scar formation is evaluated based on pliability. In some embodiments, scar formation is evaluated based on height. In some embodiments, scar formation is graded based on palpability.

[0146]

[0112] In some embodiments, the one or more positive treatment outcome is a reduction in the number of the one or more lesions. In some embodiments, the reduction in the number of the one or more lesions is a decrease of at least one lesion compared to the number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a complete absence of visual lesions compared to the number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of between 1% to 100% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 1% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 5% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 10% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 15% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 20% of the total number of lesions present in the pelvic organ beforeAtorney Docket No. 69831-701601

[0147] treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 25% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 30% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 35% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 40% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 45% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 50% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 55% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 60% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 65% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 70% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 75% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 80% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 85% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 90% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 95% of the total number of lesions present in the pelvic organ before treatment. In some embodiments, the reduction in the number of the one or more lesions is a decrease of 100% of the total number of lesions present in the pelvic organ before treatment. A decrease of 100% of the total number of lesions present in the pelvic organ before treatment is equivalent to the complete elimination of visual parts of the one or more lesions present before treatment.

[0148]

[0113] In some embodiments, the one or more positive treatment outcome is a reduction in size of the one or more lesions. In some embodiments, the reduction in size of the one or more lesions ranges from about 1mm to about 15mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 1mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 2mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 4mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 6mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 8mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 10mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 12mm. In someAtorney Docket No. 69831-701601

[0149] embodiments, the reduction in size of the one or more lesions is a reduction of about 14mm. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 15mm.

[0150]

[0114] In some embodiments, the reduction in size of the one or more lesions comprises a reduction in size of about 1% of the one or more lesions’ original size to about 100% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 1% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 5% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 10% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 15% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 20% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 30% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 40% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 50% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 60% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 70% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 80% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of about 90% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal. In some embodiments, the reduction in size of the one or more lesions is a reduction of 100% of the one or more lesions’ original size after anti-VEGF treatment and, optionally, surgical removal.

[0151]

[0115] In some embodiments, the reduction in size of the one or more lesions comprises a reduction in volume of about 1% of the one or more lesions’ original volume to about 100% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 1% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 5% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 10% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 15% of the one or more lesions’ original volume. In some embodiments, theAtorney Docket No. 69831-701601

[0152] reduction in volume of the one or more lesions is a reduction of about 20% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 30% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 40% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 50% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 60% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 70% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 80% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of about 90% of the one or more lesions’ original volume. In some embodiments, the reduction in volume of the one or more lesions is a reduction of 100% of the one or more lesions’ original volume.

[0153]

[0116] In some embodiments, the reduction in size of the one or more lesions can be graded using standardized means known in the art like the Hollander Scar Score.

[0154]

[0117] In some embodiments, the one or more positive treatment outcomes is a reduction in one or more symptoms experienced by the subject, the one or more symptoms comprising pain, redness, swelling, inflammation, itchiness, or combinations thereof. In some embodiments, the one or more symptoms is pain. The reduction in pain can be recorded using standardized means known in the art, such as the Wong-Baker FACES scale. In some embodiments, the one or more symptoms is inflammation. In some embodiments, the one or more symptoms is redness. In some embodiments, the one or more symptoms is swelling. In some embodiments, the one or more symptoms is inflammation. In some embodiments, the one or more symptoms is itchiness.

[0155]

[0118] In some embodiments, the one or more positive treatment outcomes is a prevention of vascular reappearance at the target region. In some embodiments, the prevention of vascular reappearance at the target region lasts for between 1 and 60 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for 10 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for 20 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for 30 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for 60 days.

[0156]

[0119] In some embodiments, the prevention of vascular reappearance at the target region lasts for at least 10 days . In some embodiments, the prevention of vascular reappearance at the target region lasts for at least 20 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for at least 30 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for at least 40 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for at least

[0157] 1Atorney Docket No. 69831-701601

[0158] 50 days. In some embodiments, the prevention of vascular reappearance at the target region lasts for at least 60 days.

[0159]

[0120] In some embodiments, the one or more positive treatment outcomes is a prevention of regrowth of the one or more lesions at the target region. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for between 1 and 90 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 1 day, 3 days, 5 days, 7 days, 9 days, 11 days, 13 days, 15 days, 17 days, 19 days, 21 days, 23 days, 25 days, 27 days, 29 days, 31 days, 33 days, 35 days, 37 days, 39 days, 41 days, 43 days. 45 days, 47 days, 49 days, 51 days, 53 days, 55 days, 57 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, or 90 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 15 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 30 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 45 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 60 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 75 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for 90 days.

[0160]

[0121] In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 15 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 30 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 45 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 60 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 75 days. In some embodiments, the prevention of regrowth of the one or more lesions at the target region lasts for at least 90 days.

[0161] Kit

[0162]

[0122] In another aspect, the disclosure provides a kit for treating a subject by a healthcare provider e.g., a surgeon or a physician. The kit may be packaged in a sterile package. In some aspects, the kit may comprise one or more doses of any anti-VEGF agents described herein (e.g., ranibizumab). For example, a kit may include 1, 2, 3, 4, 5 or more than 5 doses of the anti-VEGF agent. In some aspects, the kit may comprise one or more doses of the botulinum toxin A described herein (e.g., Onabotulinum toxin A). For example, a kit may include 1, 2, 3, 4, 5 or more than 5 doses of the botulinum toxin A. In some aspects, the kit may comprise optional pain medication described herein (e.g, ibuprofen). For example, a kit may include 1, 2, 3, 4, 5 or more than 5 doses of the pain medication.

[0163]

[0123] In some aspects, the biological agents (anti-VEGF agent, botulinum toxin A, and optional pain medication) may be supplied in preloaded syringes or applicators, or in vials, and may be provided in aqueous or lyophilized form, aliquoted into one or more containers included in the kit. In some aspects, the kit may also include surgical tools such as syringes, a cuting device, and an endoscope, and may contain instructions for use by a healthcare provider.Atorney Docket No. 69831-701601

[0164] III. EXAMPLES

[0165]

[0124] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0166]

[0125] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods within the scope of these claims and their equivalents be covered thereby.

[0167] Example 1: Exemplary Protocol for Treating Endometriosis with an Anti-VEGF Agent and Botulinum Toxin A

[0168]

[0126] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from endometriosis with the methods of treatment disclosed herein.

[0169]

[0127] Patient Preparation: After adequate induction of anesthesia, the pelvic cavity and abdomen can be insufflated with CO2 gas. A rigid endoscope sheath, and two additional laparoscopy port sheaths can be placed for examination and survey of the peritoneal lining and surrounding organs for evidence of ectopic endometriosis. An imaging camera can be used to capture the lesions to be treated, and their sizes and locations will be magnified on screen. Special notes can be made for any residual scar bands or adhesions from prior procedures. The procedure can begin after adequate survey and identification of all lesions to be treated.

[0170]

[0128] Lesions located in the most inferior regions of the recto-vaginal space can be operated on first, followed by lesions on the bladder, uterus, fallopian tubes, ovaries, and lateral spaces of the peritoneal cavity in ascending order.

[0171]

[0129] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fited to the flexible endoscope guide and then opened once in the abdominal cavity. The diameter of the needle array may be adjusted so that roughly 360° coverage around a lesion of interest is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion (see, for example FIG. 1) at a concentration range of 0.25-5mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion is recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.

[0172]

[0130] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection ofAtorney Docket No. 69831-701601

[0173] the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterile absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the pelvic cavity can be surveyed.

[0174]

[0131] Robot-assisted destruction and removal of the lesions may also be performed in addition to the above treatment (e.g.: DaVinci; Intuitive Surgical). The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0175]

[0132] Administration of Botulinum Toxin A: For some patients, in particular patients with a strong history of pain or opioid use, botulinum toxin A can be injected into the scar tissue bands at a concentration range of 5-30U / cm2. In addition, a row of injections can be performed along the known pelvic nerve pathways innervating the target region for a total dose ranging from 30-100U of botulinum toxin A.

[0176]

[0133] Post-Surgery: After completion of above, the abdomen and pelvic cavities can be decompressed, endoscope ports can be removed, and open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.

[0177]

[0134] Follow-up: It is expected the patient will exhibit reduced symptoms of endometriosis upon follow up. Assessment of the injection site at days 30, 60, 90, and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong-Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0178]

[0135] Patient satisfaction assessment can be performed at days 30, 60, 90 and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; or another a validated outcome measurement tool within the gynecologic literature.

[0179]

[0136] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).

[0180] Example 2: Exemplary Protocol for Treating Endometriosis with an Anti-VEGF Agent

[0181]

[0137] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from endometriosis with the methods of treatment described herein.

[0182]

[0138] Patient Preparation: After adequate induction of anesthesia, the pelvic cavity and abdomen can be insufflated with CO2 gas. A rigid endoscope sheath, and two additional laparoscopy port sheaths can be placed for examination and survey of the peritoneal lining and surrounding organs for evidence of ectopic endometriosis. An imaging camera can be used to capture the lesions to be treated, and their sizes and locations can be magnified on screen. Special notes can be made for any residual scar bands or adhesions from prior procedures. The procedure can begin after adequate survey and identification of all lesions to be treated.Atorney Docket No. 69831-701601

[0183]

[0139] Lesions located in the most inferior regions of the recto-vaginal space can be operated on first, followed by lesions on the bladder, uterus, fallopian tubes, ovaries, and lateral spaces of the peritoneal cavity in ascending order.

[0184]

[0140] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fited to the flexible endoscope guide and then opened once in the abdominal cavity. The diameter of the needle array can be adjusted so that roughly 360° coverage around a lesion of interest is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion (see, for example FIG. 1) at a concentration range of 0.25-5mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion can be recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.

[0185]

[0141] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection of the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterile absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the pelvic cavity can be surveyed.

[0186]

[0142] Robot-assisted destruction and removal of the lesions may also be performed (e.g.: DaVinci; Intuitive Surgical) in addition to the above. The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0187]

[0143] Post-Surgery: After completion of above, the abdomen and pelvic cavities can be decompressed, endoscope ports can be removed, and open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.

[0188]

[0144] Follow-up: It is expected the patient can exhibit reduced symptoms of endometriosis upon follow up. Assessment of the injection site at days 30, 60, 90, and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong-Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0189]

[0145] Patient satisfaction assessment can be performed at days 30, 60, 90, and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; a validated outcome measurement tool within the gynecologic literature.

[0190]

[0146] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).Atorney Docket No. 69831-701601

[0191] Example 3: Treatment of a Human Subject with Endometriosis

[0192]

[0147] Described here are the results of localized administered anti-VEGF agent to a 47-year-old subject presenting with an endometriosis lesion on an ovary with adhesions to the peritoneal lining. During laparoscopic surgery to remove the lesion, the lesion was first mobilized away from the pelvic wall. After mobilization, the lesion was administered the anti-VEGF agent, ranibizumab, at a dose of 0.25 mg / mL by local injection into the lesion at 0.3mL volume. The lesion was then surgically removed, bisected into a control section (away from the injection site) and an experimental section (at the injection site), and both maintained in sterile culture in RPMI-1640 with L-glutamine. After 48 hours, the tissue was placed in formalin, sliced with a microtome, and stained with either Hematoxylin & Eosin (H&E) or the endothelial cell marker CD31 (PECAM-1).

[0193]

[0148] A baseline of untreated endometrial tissue was established by resecting and culturing a control sample with no treatment (FIG. 2). Control tissue exhibited significant vascularity by H&E stain, (FIG.

[0194] 2A) and CD31 labeling (FIG. 2B), confirming the presence of substantial vascularity in endometrial lesions. A magnified view of the untreated lesion (FIG 3) showed a rich supply of endothelial cells and vascularity in the ectopic endometrial tissue via CD31 staining. The epithelial cells are simple columnar, with a mix of secretory types. The connective tissue is densely cellular and contains abundant ground substance with coiled arteries nourishing the uterine lining, as indicated by anti-CD31 labeling.

[0195]

[0149] FIG. 4 illustrates histology slides of the section that received ranibizumab injection, with low and high magnifications in FIGs. 4A and 4B, respectively. The treatment group showed low CD31 staining, indicating fewer endothelial cells compared to control tissue. Additionally, there was a marked reduction in lamina propria and ground substance, along with fibrosis and collagen deposition, consistent with decreased endometriosis mass as a result of the treatment. This method of controlling endometrial lesions through local ranibizumab injection demonstrates similar remodeling of vascular and tissue architecture as systemic intravenous treatment, which would require much higher doses (approximately 5 mg / kg) administered three times weekly over two weeks.

[0196]

[0150] FIG.5 illustrates a side-by-side comparison of histology slides from both control (FIG.5A) tissue and tissue treated with local injection of ranibizumab (FIG. 5B). Notably there was a reduction of tissue thickness as well as reduced CD31 staining of the endometrial lesion in the ranibizumab-treated sample versus the control. Additionally, disorganized collagen and hollow areas were noted where the ground substance once maintained a robust lamina propria in the treated sample.

[0197]

[0151] FIG. 6 illustrates differences in tissue characteristics through H&E staining, showing robust vascularity and ground substance in the control lesion (FIG. 6A) versus fibrosis and collagen in the treated lesion (FIG. 6B).

[0198]

[0152] FIG. 7 compares histology slides focusing on vascular architecture, with H&E staining showing reduced vascular size and number in the treated sample (FIG. 7B) versus control (FIG. 7A).Attorney Docket No. 69831-701601

[0199] Example 4: Exemplary Protocol for Treating Interstitial Cystitis with an Anti-VEGF Agent

[0200]

[0153] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from interstitial cystitis (i.e., classic, Hunner-type) with the methods of treatment disclosed herein.

[0201]

[0154] Patient Preparation: After adequate induction of anesthesia, the pelvic cavity and abdomen can be insufflated with CO2 gas. A rigid endoscope sheath, and two additional laparoscopy port sheaths can be placed for examination and survey of the peritoneal lining and surrounding organs can be performed. An imaging camera can be used to capture the lesions to be treated, and their sizes and locations can be magnified on screen. The procedure can begin after adequate survey and identification of all lesions to be treated on or around the bladder.

[0202]

[0155] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fitted to the flexible endoscope guide and then opened once in the abdominal cavity. The diameter of the needle array can be adjusted so that roughly 360° coverage around a lesion of interest (see, for example FIG. 1) is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion at a concentration of 5 mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion is recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.

[0203]

[0156] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection of the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterile absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the pelvic cavity can be surveyed.

[0204]

[0157] Robot-assisted destruction and removal of the lesions may also be performed (e.g.: DaVinci; Intuitive Surgical). The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0205]

[0158] Administration of Botulinum Toxin A: For some patients, in particular patients with a strong history of pain or opioid use, botulinum toxin A can be injected into the scar tissue bands at a concentration range of 5-30U / cm2. In addition, a row of injections can be performed along the known pelvic nerve pathways innervating the target region for a total dose ranging from 30-100U of botulinum toxin A.

[0206]

[0159] Post-Surgery: After completion of above, the abdomen and pelvic cavities can be decompressed, endoscope ports can be removed, and open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.Atorney Docket No. 69831-701601

[0207]

[0160] Follow-up: It is expected the patient can exhibit reduced symptoms of interstitial cystitis upon follow up. Assessment of injection site at days 30, 60, 90 and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to methods such as the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong -Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0208]

[0161] Patient satisfaction assessment can be performed at days 30, 60, 90, and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; or another validated outcome measurement tool within the gynecologic literature.

[0209]

[0162] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).

[0210] Example 5: Exemplary Protocol for Treating Interstitial Cystitis with an Anti-VEGF Agent

[0211]

[0163] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from interstitial cystitis (i.e., classic, Hunner-type) with the methods of treatment disclosed herein.

[0212]

[0164] Patient Preparation: After adequate induction of anesthesia, the pelvic cavity and abdomen can be insufflated with CO2 gas. A rigid endoscope sheath, and two additional laparoscopy port sheaths can be placed for examination and survey of the peritoneal lining and surrounding organs can be performed. An imaging camera can be used to capture the lesions to be treated, and their sizes and locations can be magnified on screen. The procedure can begin after adequate survey and identification of all lesions to be treated on or around the bladder.

[0213]

[0165] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fited to the flexible endoscope guide and then opened once in the abdominal cavity. The diameter of the needle array can be adjusted so that roughly 360° coverage around a lesion of interest (see, for example FIG. 1) is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion at a concentration of 5 mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion is recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.

[0214]

[0166] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection of the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterileAtorney Docket No. 69831-701601

[0215] absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the pelvic cavity can be surveyed.

[0216]

[0167] Optional: Robot-assisted destruction and removal of the lesions may also be performed (e.g.: DaVinci; Intuitive Surgical). The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0217]

[0168] Post-Surgery: After completion of above, the abdomen and pelvic cavities can be decompressed, endoscope ports can be removed, and open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.

[0218]

[0169] Follow-up: It is expected the patient can exhibit reduced symptoms of interstitial cystitis upon follow up. Assessment of the injection site at days 30, 60, 90, and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong-Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0219]

[0170] Patient satisfaction assessment can be performed at days 30, 60, 90, and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; a validated outcome measurement tool within the gynecologic literature.

[0220]

[0171] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).

[0221] Example 6: Exemplary Protocol for Treating Lichen Sclerosus with an Anti-VEGF Agent

[0172] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from Lichen sclerosus in the recto-vaginal area with the methods of treatment disclosed herein.

[0222]

[0173] Patient Preparation: After adequate induction of anesthesia (if necessary), an imaging camera can be used to capture the lesions to be treated, and their sizes and locations can be magnified on screen. Special notes can be made for any residual scar bands or adhesions from prior procedures. The procedure can begin after adequate survey and identification of all lesions to be treated.

[0223]

[0174] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fited to the flexible endoscope guide and then opened once in place. The diameter of the needle array can be adjusted so that roughly 360° coverage around a lesion of interest (see, for example FIG. 1) is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion at a concentration of 3.5 mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion is recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.Atorney Docket No. 69831-701601

[0224]

[0175] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection of the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterile absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the genitourinary area can be surveyed.

[0225]

[0176] Optional: Robot-assisted destruction and removal of the lesions may also be performed (e.g.: DaVinci; Intuitive Surgical). The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0226]

[0177] Administration of Botulinum Toxin A: For some patients, in particular patients with a strong history of pain or opioid use, botulinum toxin A can be injected into the scar tissue bands at a concentration range of 5-30U / cm2. In addition, a row of injections can be performed along the known pelvic nerve pathways innervating the target region for a total dose ranging from 30-100U of botulinum toxin A.

[0227]

[0178] Post-Surgery: After completion of above, open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.

[0228]

[0179] Follow-up: It is expected the patient can exhibit reduced symptoms of Lichen sclerosus upon follow up. Assessment of injection site at days 30, 60, 90, and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong-Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0229]

[0180] Patient satisfaction assessment can be performed at days 30, 60, 90, and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; a validated outcome measurement tool within the gynecologic literature.

[0230]

[0181] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).

[0231] Example 7: Exemplary Protocol for Treating Lichen Sclerosus with an Anti-VEGF Agent

[0182] Described herein is a summary of an exemplary clinical protocol for treating a patient suffering from Lichen sclerosus in the recto-vaginal area with the methods of treatment disclosed herein.

[0232]

[0183] Patient Preparation: After adequate induction of anesthesia (if necessary), an imaging camera can be used to capture the lesions to be treated, and their sizes and locations can be magnified on screen. SpecialAtorney Docket No. 69831-701601

[0233] notes can be made for any residual scar bands or adhesions from prior procedures. The procedure can begin after adequate survey and identification of all lesions to be treated.

[0234]

[0184] Administration of the Anti-VEGF Agent: A multi-port needle array (e.g.: InstaFan™; One Pass Medical) can be fited to the flexible endoscope guide and then opened once in place. The diameter of the needle array can be adjusted so that roughly 360° coverage around a lesion of interest (see, for example FIG. 1) is achieved. anti-VEGF agent can be injected through the needle array in a halo-like fashion at a concentration of 3.5 mg / ml in volume of 1 ml per square cm of wound bed. Each lesion can be treated with adequate agent and the push volume for each lesion is recorded. The process can be repeated until all identified lesions have been injected. The anti-VEGF agent can comprise any of the anti-VEGF agents recited herein.

[0235]

[0185] Surgical Removal of Lesions: A dissecting waterjet (e.g.: AquaBeam®; PROCEPT BioRobotics) can be placed in the appropriate laparoscopy port. The water jet can be employed to circumscribe and dissect the lesion for complete removal. Any dissected tissue can be removed via suction catheter. The base of the resection site can then be lightly cauterized with either a CO2 coupler (e.g.: ACCU-Beam®; Clarion Medical Technologies) or an electrosurgical unit (GI4000; Steris Healthcare). One additional injection of the anti-VEGF agent can then made directly into the wound bed followed by placement of a sterile absorbable (e.g.: Gelfoam®; Pfizer) to stop bleeding. The process can be repeated until all identified lesions have been removed. Once all lesions are treated a review of scar bands in the genitourinary area can be surveyed.

[0236]

[0186] Optional: Robot-assisted destruction and removal of the lesions may also be performed (e.g.: DaVinci; Intuitive Surgical). The surgeon can instead be seated at a console and directing the endoscopy tools and mechanisms via joystick operation.

[0237]

[0187] Post-Surgery: After completion of above, open skin can be sutured before allowing the patient to awaken from their anesthetic. Patient can then be transported to recovery area for monitoring and discharge planning.

[0238]

[0188] Follow-up: It is expected the patient can exhibit reduced symptoms of Lichen sclerosus upon follow up. Assessment of injection site at days 30, 60, 90, and 180 days via ultrasound or direct observation can be performed to access palpability, inflammation, hematoma, scar formation, lesion count and size. Scar can be scored according to the Hollander Scar Score with an additional metric for palpability of the lesion. Pain can be scored using a Wong-Baker FACES scale aligned with a numeric pain rating scale. Monitoring for the disappearance of the lesions with no regrowth can be performed, accompanied with measurement and photography.

[0239]

[0189] Patient satisfaction assessment can be performed at days 30, 60, 90 and 180 post-surgery compared to baseline, based on quality-of-life module evaluation survey; a validated outcome measurement tool within the gynecologic literature.

[0240]

[0190] Long term outcomes: Follow up examinations can occur up to 5 years after initial treatment. Additional administrations of the anti-VEGF agent may be performed for various reasons within this time period (for instance to prevent recurrence).Attorney Docket No. 69831-701601

[0241] IV. ADDITIONAL EMBODIMENTS

[0242] Embodiment 1 A method of treating an inflammatory condition of a pelvic organ of a subject, comprising administering an anti-vascular endothelial growth factor (anti-VEGF) agent to a target region in the pelvic organ and wherein the target region comprises one or more lesions or scar tissue.

[0243] Embodiment 2 The method of Embodiment 1, wherein the subject is a human subject.

[0244] Embodiment 3 The method of Embodiment 2, wherein the human subject is post-menopausal.

[0245] Embodiment 4 The method of Embodiment 2, wherein the human subject is menopausal.

[0246] Embodiment 5 The method of Embodiment 2, wherein the human subject is of a reproductive age. Embodiment 6 The method of Embodiment 2, wherein the target region is a female reproductive organ and / or female genitalia.

[0247] Embodiment 7 The method of any one of the preceding Embodiments, wherein the pelvic organ is selected from a group consisting of: uterus, peritoneal cavity, rectovaginal area, bladder wall, bladder mucosa, vaginal interior, vaginal exterior, anus, ovary, and fallopian tube.

[0248] Embodiment 8 The method of any one of the preceding Embodiments, wherein the target region comprises scar tissue caused by the one or more lesions.

[0249] Embodiment 9 The method of Embodiment 8, wherein the scar tissue is a wound bed remaining after a surgical removal of one or more lesions from the target region.

[0250] Embodiment 10 The method of any one of Embodiments 1-9, wherein the target region comprises one or more lesions.

[0251] Embodiment 11 The method of Embodiment 10, wherein the target region comprises two lesions. Embodiment 12 The method of Embodiment 10 or 11, wherein each lesion is at most about 5cm2in size.

[0252] Embodiment 13 The method of Embodiment 10 or 11, wherein each lesion is about 5cm2, about 4cm2, about 3cm2, about 2cm2, or about 1cm2in size.

[0253] Embodiment 14 The method of any one of the preceding Embodiments, wherein the inflammatory condition of a pelvic organ is selected from the group consisting of: endometriosis, fibroids, pelvic inflammatory disease (PID), endometritis, interstitial cystitis, intrauterine adhesions (Asherman’s syndrome) and inflammatory myofibroblastic tumors (IMTs).

[0254] Embodiment 15 The method of any one of the preceding Embodiments, wherein the treating of an inflammatory condition of a pelvic organ comprises a reduction in one or more symptoms experienced by the human subject, wherein the one or more symptoms are selected from the group consisting of pain, redness, swelling, inflammation, and itchiness.

[0255] Embodiment 16 The method of any one of the preceding Embodiments, wherein the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

[0256] Embodiment 17 The method of Embodiment 16, wherein the anti-VEGF agent is a protein.

[0257] Embodiment 18 The method of Embodiment 17, wherein the protein is an antibody or antigen-binding portion thereof.

[0258] Embodiment 19 The method of Embodiment 18, wherein the antibody is a monoclonal antibody.Atorney Docket No. 69831-701601

[0259] Embodiment 20 The method of Embodiment 19, wherein the antibody is bevacizumab or antigenbinding portion thereof, or an agent with a clinical efficacy or function comparable to bevacizumab. Embodiment 21 The method of Embodiment 19, wherein the antibody is ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab.

[0260] Embodiment 22 The method of any one of Embodiments 19-21, wherein the administering of the anti-VEGF agent comprises injecting one or more doses of the anti-VEGF agent to the target region.

[0261] Embodiment 23 The method of Embodiment 22, further comprising administering (e.g., by injection) more than one dose of the anti-VEGF agent per lesion.

[0262] Embodiment 24 The method of Embodiment 22 or Embodiment 23, wherein one dose of the anti-VEGF agent is at least 0.1 mg per cm2of the target region.

[0263] Embodiment 25 The method of any one of Embodiments 22-24, wherein one dose of the anti-VEGF agent is at most 5 mg per cm2of the target region.

[0264] Embodiment 26 The method of Embodiment 19, wherein one dose of the anti-VEGF agent is from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region.

[0265] Embodiment 27 The method of any one of Embodiments 19-26, wherein a total dose of the anti-VEGF agent administered is at most 50mg.

[0266] Embodiment 28 The method of any one of the preceding Embodiments, wherein the anti-VEGF agent is isolated from an organism.

[0267] Embodiment 29 The method of any one of the preceding Embodiments, wherein the anti-VEGF agent is produced using recombinant expression of the anti-VEGF agent in the organism.

[0268] Embodiment 30 The method of any one of the preceding Embodiments, wherein the method further comprises surgical removal of the one more lesions from the target region.

[0269] Embodiment 31 The method of Embodiment 30, wherein the surgical removal of the one or more lesions is performed prior to the administering of the anti-VEGF agent.

[0270] Embodiment 32 The method of Embodiment 30, wherein the surgical removal of the one or more lesions is performed concurrently with the administering of the anti-VEGF agent.

[0271] Embodiment 33 The method of Embodiment 30, wherein the surgical removal of the one or more lesions is performed after the administering of the anti-VEGF agent.

[0272] Embodiment 34 The method of any one of Embodiments 30-33, wherein the surgical removal is performed with minimally invasive surgery.

[0273] Embodiment 35 The method of Embodiment 34, wherein the minimally invasive surgery is robotic surgery.

[0274] Embodiment 36 The method of Embodiments 34 or 35, wherein the minimally invasive surgery is laparoscopic surgery.

[0275] Embodiment 37 The method of any one of Embodiments 30-36, wherein the lesions are removed partially based on photograph visualization.

[0276] Embodiment 38 The method of any one of the preceding Embodiments, wherein the method further comprises administering one or more pain relief medications to the human subject.Atorney Docket No. 69831-701601

[0277] Embodiment 39 The method of Embodiment 38, wherein the one or more pain relief medication is oral pain relief medication.

[0278] Embodiment 40 The method of Embodiment 39, wherein the oral pain relief medications are selected from analgesics, NSAIDs and opioids.

[0279] Embodiment 41 The method of any one of Embodiments 38-40, wherein the method further comprises administering agents capable of reducing scar tissue adhesion.

[0280] Embodiment 42 The method of any one of the preceding Embodiments, wherein administering of the anti-VEGF agent to the target region is localized administration via syringe injection.

[0281] Embodiment 43 The method of Embodiment 42, wherein the administering of the anti-VEGF agent is directed within the one or more lesions.

[0282] Embodiment 44 The method of any one of Embodiments 42-43, wherein the administering of the anti-VEGF agent is directed within the wound bed remaining post-surgical removal of the one or more lesions from the target region.

[0283] Embodiment 45 The method of any one of Embodiments 42-44, wherein the administering of the anti-VEGF agent is directed to the periphery of the one or more lesions.

[0284] Embodiment 46 The method of any one of the preceding Embodiments, wherein the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 10% as compared to a size of the lesion before the administration.

[0285] Embodiment 47 The method of Embodiment 46, wherein the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 15%, 20%, 25%, 30%, 40% 50%, 60%, 70%, or 80% as compared to a size of the lesion before the administration.

[0286] Embodiment 48 The method of any one of the preceding Embodiments, wherein the administration of anti-VEGF agent results in a reduction in the number of the one or more lesions present in the target region before treatment.

[0287] Embodiment 49 The method of any of the preceding Embodiments, wherein the method further comprises administering one or more doses of botulinum toxin A.

[0288] Embodiment 50 The method of Embodiment 49, wherein the one or more doses of botulinum toxin A is administered to pelvic nerves innervating the target region.

[0289] Embodiment 51 The method of Embodiment 49, wherein the botulinum toxin A is isolated from an organism.

[0290] Embodiment 52 The method of any one of Embodiments 49-51, wherein the botulinum toxin A is produced using recombinant expression of the botulinum toxin A in the organism.

[0291] Embodiment 53 The method of any one of Embodiments 49-52 wherein the botulinum toxin A is selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

[0292] Embodiment 54 A method of treating endometriosis in a subject, comprising administering an anti-vascular endothelial growth factor (anti-VEGF) agent to a target region in a uterus of the subject and wherein the target region comprises one or more lesions or scar tissue caused by one or more lesions.Attorney Docket No. 69831-701601

[0293] Embodiment 55 The method of Embodiment 54, wherein a single dose of the anti-VEGF agent is administered in the target region.

[0294] Embodiment 56 The method of Embodiment 55, wherein one dose of the anti-VEGF agent is from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region.

[0295] Embodiment 57 The method of any one of Embodiments 54-56, wherein more than one dose of the anti-VEGF agent is administered to the subject.

[0296] Embodiment 58 The method of Embodiment 54, further comprising surgical removal of the one or more lesions from the uterus.

[0297] Embodiment 59 The method of any one of Embodiments 54-58, wherein the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

[0298] Embodiment 60 The method of Embodiment 59, wherein the anti-VEGF agent is a protein.

[0299] Embodiment 61 The method of Embodiment 60, wherein the protein is an antibody.

[0300] Embodiment 62 The method of Embodiment 61, wherein the antibody is a monoclonal antibody. Embodiment 63 The method of Embodiment 62, wherein the antibody is bevacizumab, or an agent with a clinical efficacy or function comparable to bevacizumab.

[0301] Embodiment 64 The method of Embodiment 62, wherein the antibody is ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab.

[0302] Embodiment 65 The method of any one of Embodiments 54-64, further comprising administering one or more doses of botulinum toxin A.

[0303] Embodiment 66 The method of Embodiment 65, wherein the botulinum toxin A is selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

[0304] Embodiment 67 A method of treating interstitial cystitis in a subject, comprising administering an anti-vascular endothelial growth factor (anti-VEGF) agent to a target region in a bladder of the subject and wherein the target region comprises one or more lesions or scar tissue caused by one or more lesions. Embodiment 68 The method of Embodiment 67, wherein a single dose of the anti-VEGF agent is administered in the target region.

[0305] Embodiment 69 The method of Embodiment 68, wherein one dose of the anti-VEGF agent is from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region.

[0306] Embodiment 70 The method of any one of Embodiments 67-69, wherein more than one dose of the anti-VEGF agent is administered to the subject.

[0307] Embodiment 71 The method of Embodiment 67, further comprising surgical removal of the one or more lesions from the bladder mucosa.

[0308] Embodiment 72 The method of any one of Embodiments 67-71 wherein the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

[0309] Embodiment 73 The method of Embodiment 72, wherein the anti-VEGF agent is a protein.

[0310] Embodiment 74 The method of Embodiment 73, wherein the protein is an antibody.

[0311] Embodiment 75 The method of Embodiment 74, wherein the antibody is a monoclonal antibody.Attorney Docket No. 69831-701601

[0312] Embodiment 76 The method of Embodiment 75, wherein the antibody is bevacizumab, or an agent with a clinical efficacy or function comparable to bevacizumab.

[0313] Embodiment 77 The method of Embodiment 75, wherein the antibody is ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab.

[0314] Embodiment 78 The method of any one of Embodiments 67-77, further comprising administering one or more doses of botulinum toxin A.

[0315] Embodiment 79 The method of Embodiment 78 wherein the botulinum toxin A is selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

[0316] Embodiment 80 A method of treating lichen sclerosus in a subject, comprising administering an anti-vascular endothelial growth factor (anti-VEGF) agent to a target region on a vagina of the subject and wherein the target region comprises one or more lesions or scar tissue caused by one or more lesions. Embodiment 81 The method of Embodiment 80, wherein a single dose of the anti-VEGF agent is administered in the target region.

[0317] Embodiment 82 The method of Embodiment 81, wherein one dose of the anti-VEGF agent is from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region.

[0318] Embodiment 83 The method of any one of Embodiments 80-82, wherein more than one dose of the anti-VEGF agent is administered to the subject.

[0319] Embodiment 84 The method of Embodiment 80, further comprising surgical removal of the one or more lesions from the bladder mucosa.

[0320] Embodiment 85 The method of any one of Embodiments 80-84 wherein the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

[0321] Embodiment 86 The method of Embodiment 85, wherein the anti-VEGF agent is a protein.

[0322] Embodiment 87 The method of Embodiment 86, wherein the protein is an antibody.

[0323] Embodiment 88 The method of Embodiment 87, wherein the antibody is a monoclonal antibody. Embodiment 89 The method of Embodiment 88, wherein the antibody is bevacizumab, or an agent with a clinical efficacy or function comparable to bevacizumab.

[0324] Embodiment 90 The method of Embodiment 88, wherein the antibody is ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab.

[0325] Embodiment 91 The method of any one of Embodiments 80-90, further comprising administering one or more doses of botulinum toxin A.

[0326] Embodiment 92 The method of Embodiment 91 wherein the botulinum toxin A is selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

Claims

1. Attorney Docket No. 69831-701601CLAIMS1. A method of treating an inflammatory condition of a pelvic organ of a subject, comprising administering an anti-vascular endothelial growth factor (anti-VEGF) agent to a target region in the pelvic organ and wherein the target region comprises one or more lesions or scar tissue.

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

3. The method of claim 2, wherein the human subject is post-menopausal.

4. The method of claim 2, wherein the human subject is menopausal.

5. The method of claim 2, wherein the human subject is of a reproductive age.

6. The method of claim 2, wherein the target region is a female reproductive organ and / or female genitalia.

7. The method of any one of the preceding claims, wherein the pelvic organ is selected from a group consisting of: uterus, peritoneal cavity, rectovaginal area, bladder wall, bladder mucosa, vaginal interior, vaginal exterior, anus, ovary, and fallopian tube.

8. The method of any one of the preceding claims, wherein the target region comprises scar tissue caused by the one or more lesions.

9. The method of claim 8, wherein the scar tissue is a wound bed remaining after a surgical removal of one or more lesions from the target region.

10. The method of any one of claims 1-9, wherein the target region comprises one or more lesions.

11. The method of claim 10, wherein the target region comprises two lesions.

12. The method of claim 10 or 11, wherein each lesion is at most about 5cm2in size.

13. The method of claim 10 or 11, wherein each lesion is about 5cm2, about 4cm2, about 3cm2, about 2cm2, or about 1cm2in size.

14. The method of any one of the preceding claims, wherein the inflammatory condition of a pelvic organ is selected from the group consisting of: endometriosis, fibroids, pelvic inflammatory disease (PID), endometritis, interstitial cystitis, intrauterine adhesions (Asherman’s syndrome) and inflammatory myofibroblastic tumors (IMTs).

15. The method of any one of the preceding claims, wherein the treating of an inflammatory condition of a pelvic organ comprises a reduction in one or more symptoms experienced by the human subject, wherein the one or more symptoms are selected from the group consisting of pain, redness, swelling, inflammation, and itchiness.

16. The method of any one of the preceding claims, wherein the anti-VEGF agent is selected from: small molecules, proteins, oligonucleotides, and peptides.

17. The method of claim 16, wherein the anti-VEGF agent is a protein.Atorney Docket No. 69831-70160118. The method of claim 17, wherein the protein is an antibody or antigen-binding portion thereof.

19. The method of claim 18, wherein the antibody is a monoclonal antibody.

20. The method of claim 19, wherein the antibody is bevacizumab or antigen-binding portion thereof, or an agent with a clinical efficacy or function comparable to bevacizumab.

21. The method of claim 19, wherein the antibody is ranibizumab, or an agent with a clinical efficacy or function comparable to ranibizumab.

22. The method of any one of claims 19-21, wherein the administering of the anti-VEGF agent comprises injecting one or more doses of the anti-VEGF agent to the target region.

23. The method of claim 22, further comprising administering (e.g., by injection) more than one dose of the anti-VEGF agent per lesion.

24. The method of claim 22 or claim 23, wherein one dose of the anti-VEGF agent is at least 0.1 mg per cm2of the target region.

25. The method of any one of claims 22-24, wherein one dose of the anti-VEGF agent is at most 5 mg per cm2of the target region.

26. The method of claim 19, wherein one dose of the anti-VEGF agent is from about 0.25mg per cm2of the target region to about 5mg per cm2of the target region.

27. The method of any one of claims 19-26, wherein a total dose of the anti-VEGF agent administered is at most 50mg.

28. The method of any one of the preceding claims, wherein the anti-VEGF agent is isolated from an organism.

29. The method of any one of the preceding claims, wherein the anti-VEGF agent is produced using recombinant expression of the anti-VEGF agent in the organism.

30. The method of any one of the preceding claims, wherein the method further comprises surgical removal of the one more lesions from the target region.

31. The method of claim 30, wherein the surgical removal of the one or more lesions is performed prior to the administering of the anti-VEGF agent.

32. The method of claim 30, wherein the surgical removal of the one or more lesions is performed concurrently with the administering of the anti-VEGF agent.

33. The method of claim 30, wherein the surgical removal of the one or more lesions is performed after the administering of the anti-VEGF agent.

34. The method of any one of claims 30-33, wherein the surgical removal is performed with minimally invasive surgery.

35. The method of claim 34, wherein the minimally invasive surgery is robotic surgery.Atorney Docket No. 69831-70160136. The method of claims 34 or 35, wherein the minimally invasive surgery is laparoscopic surgery.

37. The method of any one of claims 30-36, wherein the lesions are removed partially based on photograph visualization.

38. The method of any one of the preceding claims, wherein the method further comprises administering one or more pain relief medications to the human subject.

39. The method of claim 38, wherein the one or more pain relief medication is oral pain relief medication.

40. The method of claim 39, wherein the oral pain relief medications are selected from analgesics, NSAIDs and opioids.

41. The method of any one of claims 38-40, wherein the method further comprises administering agents capable of reducing scar tissue adhesion.

42. The method of any one of the preceding claims, wherein administering of the anti-VEGF agent to the target region is localized administration via syringe injection.

43. The method of claim 42, wherein the administering of the anti-VEGF agent is directed within the one or more lesions.

44. The method of any one of claims 42-43, wherein the administering of the anti-VEGF agent is directed within the wound bed remaining post-surgical removal of the one or more lesions from the target region.

45. The method of any one of claims 42-44, wherein the administering of the anti-VEGF agent is directed to the periphery of the one or more lesions.

46. The method of any one of the preceding claims, wherein the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 10% as compared to a size of the lesion before the administration.

47. The method of claim 46, wherein the administration of anti-VEGF agent results in the reduction in size of the one or more lesions by at least 15%, 20%, 25%, 30%, 40% 50%, 60%, 70%, or 80% as compared to a size of the lesion before the administration.

48. The method of any one of the preceding claims, wherein the administration of anti-VEGF agent results in a reduction in the number of the one or more lesions present in the target region before treatment.

49. The method of any of the preceding claims, wherein the method further comprises administering one or more doses of botulinum toxin A.

50. The method of claim 49, wherein the one or more doses of botulinum toxin A is administered to pelvic nerves innervating the target region.

51. The method of claim 49, wherein the botulinum toxin A is isolated from an organism.Atorney Docket No. 69831-70160152. The method of any one of claims 49-51, wherein the botulinum toxin A is produced using recombinant expression of the botulinum toxin A in the organism.

53. The method of any one of claims 49-52 wherein the botulinum toxin A is selected from the following: Onabotulinum toxin A, Incobotulinum toxin A, Abobotulinum toxin A, Prabobotulinum Toxin A, and Daxibotulinum toxin A.

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