Methods and compositions for treating diseases and conditions associated with gonadotropin releasing hormone receptor

#Polycystic Ovary Syndrome (PCOS) is a systemic disease characterized by multiple ovarian cysts, infertility, pain, discomfort, and associated metabolic abnormalities including insulin resistant diabetes mellitus, abnormal sex hormone function, hirsutism, and acne. It is considered of unknown etiology and frequently occurs in adolescence. PCOS involves the pituitary-ovarian reproductive organs, resulting in anovulatory infertility in 8-10% of women of reproductive age. Its causation is currently unknown but is associated with abnormal pituitary control and/or release of both luteinizing hormone (LH) and follicle stimulating hormone (FSH), both of which are intimately related to development and release of ova from the ovary in timely fashion for possible fertilization when a viable sperm is in proximity. In this condition, the release of the developing ova is severely impaired and generally is internally reabsorbed without release. The developing follicle continues to be stimulated by this abnormal absence of rupture and release and becomes a persistent and enlarged cyst leading to distortion of the ovarian architecture and further disturbing normal development of subsequent follicles.

#This infertility is profound in many conditions leading to heartbreak, frustration, self-recrimination, and marital discord. Current infertility therapies are frustratingly of low success, and current state of the art resides in in vitro fertilization, often requiring a separate donor and emplacement of the embryo. The costs are very high (e.g., $75K for three attempts) and are without guarantee of issue. Moreover, PCOS is not just an issue of infertility, as a significant majority of these women develop a complex syndrome over several years that includes obesity, significant insulin resistance manifested by Type 2 diabetes mellitus, hypertension, and signs of hyper-androgenism (elevation of testosterone and weak androgens) including acne and hirsutism. A smaller subgroup includes women of thin nature despite eating freely yet who do not develop the above-mentioned metabolic syndrome. These women nevertheless share in the infertility and polycystic ovary presentation. This metabolic syndrome that is so prevalent must be treated using multiple dietary and pharmacological approaches. The diabetes has most commonly been treated with metformin with modest improvement, despite the frequent side effects of the medication and its long term inability to cure the disease. Interestingly, in some subjects there is minimal or very modest improvement in the infertility but this is not common. Newer diabetes medications are being tried but have significant costs and are not recognized as more effective than metformin on the infertility. The hypertension is treated with usually more than one antihypertensive agent with their concomitant cost and side effects. The hyper-androgen state is of particular concern for women of all ages but is especially devastating for young women in society. The therapy usually is started too late and or inadequately and consists of birth control pill (BCP) therapy to suppress LH and the use of androgen receptor antagonists with their concurrent side effects and expense. Alterations in gonadotropin releasing hormone (GnRH) or its receptor (GnRHR) have not been successfully associated with causation.

#FIG. 1A shows the ELISA O.D. (vertical axis) directed against the GnRHR-extracellular loop 2 (ECL2) sequence for the PCOS for serum from infertile but ovulatory control subjects. The values in the left panel were assayed initially and subsequently repeated after a 5 mo. interval with storage at 4° C. The PCOS values were significantly higher than the controls on both assays, with a p=0.003 and 0.005, respectively. The slight decrease in n for the assay in the second panel was due to insufficient sera in one PCOS subject and two control subjects. The dashed line represents+2 SD of the controls. The solid line is the mean for each group.

#FIG. 1B shows an ELISA assay of these subjects using the GnRHR-ECL1 sequence. There was no evidence for an Ab directed toward this adjacent ECL (extracellular loop).

#FIG. 1C shows a ROC curve comparing the ELISA OD assayed in the PCOS and control subjects (data are from the right panel of FIG. 1A). There is a sensitivity of 72% and a specificity of 55% compared to a theoretical control population (dashed line). The area under the curve was significantly different from the controls (p=0.0013). Diagonal segments are produced by ties. These were subjects matched for age and BMR and blinded to the lab.

#The present disclosure is directed, in at least certain embodiments, to compositions and methods of treating conditions and diseases associated with activation of the gonadotropin GnRH receptor (GnRHR), particularly (but not limited to) those involving GnRHR activating autoantibodies (GnRHR AAbs). A particular (but non-limiting) novel feature of the present disclosure is the discovery of the relationship of GnRHR AAbs and Polycystic Ovary Syndrome. Therefore, in at least one embodiment, the present disclosure is directed to treatment of PCOS by the therapeutic clearing of GnRHR AAbs from the circulation. The therapeutic compounds in at least certain embodiments include peptides at least partially comprising D-amino acids, and in further embodiments include retro-inverso D-amino acid (RID) peptides, which are able to bind with high affinity to GnRHR AAbs, thereby inhibiting the binding of the GnRHR AAbs to GnRHR via competitive inhibition.

#Without wishing to be bound by theory, it is believed that activating autoantibodies (GnRHR AAbs) which bind to the extracellular loop 2 (ECL2) of GnRHR are produced from an extraneous stimulus (e.g., an infection, stress, etc.) and interact with hypothalamic/pituitary GnRH receptors to inappropriately alter the synthesis and periodic release of LH, leading to hyperandrogenemia, induction of insulin resistance (IR), and metabolic complications.

#Before further describing various embodiments of the present disclosure in more detail by way of exemplary description, examples, and results, it is to be understood that the compounds, compositions, and methods of present disclosure are not limited in application to the details of specific embodiments and examples as set forth in the following description. The description provided herein is intended for purposes of illustration only and is not intended to be construed in a limiting sense. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments and examples are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the present disclosure. However, it will be apparent to a person having ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. It is intended that all alternatives, substitutions, modifications, and equivalents apparent to those having ordinary skill in the art are included within the scope of the present disclosure. Thus, while the compounds, compositions, and methods of the present disclosure have been described in terms of particular (but non-limiting) embodiments, it will be apparent to those of skill in the art that variations may be applied to the compounds, compositions, and methods, and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the inventive concepts.