Search

CN-122005600-A - Application of AMPD3 gene expression inhibitor in preparation of medicines for preventing and treating polycystic ovary syndrome

CN122005600ACN 122005600 ACN122005600 ACN 122005600ACN-122005600-A

Abstract

The invention belongs to the technical field of medicines, and discloses application of an AMPD3 gene expression inhibitor in preparing a medicine for preventing, relieving and/or treating polycystic ovary syndrome. The AMPD3 gene expression inhibitor is a nucleic acid molecule targeting the AMPD3 gene sequence or a recombinant vector comprising the nucleic acid molecule. The invention reduces the iron death level of ovarian granulosa cells, up-regulates GPX4 expression and reduces MDA level by inhibiting AMPD3 gene expression, thereby improving the morphological abnormality of the ovary and the metabolic disorder of reproductive endocrine. The invention provides a new treatment strategy for patients with polycystic ovary syndrome.

Inventors

  • YAN SISI
  • QIU HUI
  • Sun shaoxing
  • Wu Qiuji
  • CHEN MIN
  • MEI ZIJIE
  • YANG CHUNXU
  • XIANG QINGMING

Assignees

  • 武汉大学中南医院

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. Use of an AMPD3 gene expression inhibitor for the manufacture of a medicament for the prevention, alleviation and/or treatment of polycystic ovary syndrome.
  2. 2. The method of claim 1, wherein the inhibitor of AMPD3 gene expression is a nucleic acid molecule targeting the AMPD3 gene sequence or a recombinant vector comprising said nucleic acid molecule.
  3. 3. The use according to claim 2, characterized in that: The nucleic acid molecule is siRNA or shRNA, and/or, The recombinant vector is a non-viral vector or a viral vector.
  4. 4. The use according to claim 1, wherein the patient suffering from polycystic ovary syndrome has one or more of the following pathological characteristics: An abnormal ovarian granulosa cell iron death indicator selected from one or more of reduced glutathione peroxidase 4 expression levels, increased lipid peroxide malondialdehyde levels, reduced glutathione levels, and reduced mitochondrial membrane potential; an abnormality in an ovarian morphology index selected from one or more of reduced number of functional sinus follicles, reduced number of corpus luteum, and increased number of follicular follicles; Abnormal reproductive endocrine and metabolic indicators selected from one or more of estrus cycle or menstrual cycle disorder, elevated serum luteinizing hormone levels, elevated serum testosterone levels, and reduced blood glucose abnormalities or insulin sensitivity.
  5. 5. The method according to claim 1, wherein the prevention, alleviation and/or treatment of polycystic ovary syndrome is manifested by one or more of the following: The expression level of glutathione peroxidase 4 in the ovary granular cells is increased; Reduced levels of malondialdehyde in ovarian granulosa cells; elevated glutathione levels in ovarian granulosa cells; Mitochondrial membrane potential is elevated in ovarian granulosa cells.
  6. 6. The method according to claim 1, wherein the prevention, alleviation and/or treatment of polycystic ovary syndrome is manifested by one or more of the following: the number of sinus follicles increases; the number of corpus luteum increases; The number of saccular follicles decreases.
  7. 7. The method according to claim 1, wherein the prevention, alleviation and/or treatment of polycystic ovary syndrome is manifested by one or more of the following: an improvement in estrus cycle or menstrual cycle disorders; Reduced serum luteinizing hormone levels; reduced serum testosterone levels; blood glucose or insulin sensitivity is improved.
  8. 8. The method according to claim 1, wherein the pharmaceutical composition is in the form of an ovarian in-situ injection, a systemic injection or an oral preparation.
  9. 9. A pharmaceutical composition for preventing, relieving and/or treating polycystic ovary syndrome is characterized by comprising an AMPD3 gene expression inhibitor and pharmaceutically acceptable auxiliary materials.
  10. 10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises at least one additional active ingredient selected from the group consisting of metformin, clomiphene, letrozole, and oral contraceptives.

Description

Application of AMPD3 gene expression inhibitor in preparation of medicines for preventing and treating polycystic ovary syndrome Technical Field The invention belongs to the field of medicines, and relates to an adenylate deaminase 3 (AMPD 3) inhibitor, a pharmaceutical composition containing the same and application of the same in preparation of medicines for preventing and treating polycystic ovary syndrome. Background Polycystic ovary syndrome (Polycystic Ovary Syndrome, PCOS) is the most common endocrine metabolic disorder in women of childbearing age and is mainly characterized by ovulation disorders, hyperandrogenism and polycystic ovary-like alterations. PCOS not only causes female infertility, but also significantly increases the risk of patients suffering from type 2 diabetes, cardiovascular disease and endometrial cancer. Currently, clinical treatment strategies for PCOS are mainly focused on symptom management. For example, oral contraceptives are used to regulate the menstrual cycle and reduce androgen levels, metformin is used to improve insulin resistance, or ovulation is induced using ovulation-promoting drugs. However, these existing therapies mostly interfere with downstream phenotypes and it is difficult to radically reverse pathological lesions of ovarian function. Particularly for the core pathological basis of ovarian granulosa cell dysfunction which leads to follicular development retardation, an effective specific therapeutic target is lacking at present. Furthermore, the safety, tolerability, and anergy of some patients with long-term use of existing drugs remains a clinical challenge. In recent years, iron cell death (Ferroptosis) has been found to be associated with a variety of reproductive disorders as a novel means of programmed cell death. Studies have shown that oxidative stress and lipid peroxidation abnormalities exist in ovarian granulosa cells of PCOS patients, suggesting that iron death may be involved in the pathological processes of PCOS. However, the upstream key molecular mechanisms that regulate the death of granular cellular iron are not yet defined. Although AMPD3 is known to be a key rate-limiting enzyme in the purine metabolic pathway responsible for catalyzing deamination of Adenylate (AMP) to inosinic acid (IMP), the expression profile of AMPD3 in ovarian tissue and its role in PCOS pathogenesis have not been reported at present. Furthermore, existing PCOS diagnostics and therapies lack specific molecular markers. Clinically, hormone levels (such as LH/FSH ratio and testosterone) and ultrasonic morphological examination are mainly relied on, and the indexes often become abnormal after the disease progresses to a certain stage and cannot reflect early pathological changes at the cellular level. Therefore, searching a new target capable of specifically regulating and controlling the survival of granulosa cells and improving the ovarian microenvironment and developing a drug based on the target has become a technical problem to be solved in the field of PCOS treatment. Disclosure of Invention The present invention found that AMPD3 expression was significantly up-regulated in granulosa cells of PCOS patients. The death of the granulosa cell iron can be obviously reduced after the AMPD3 gene is knocked down in the granulosa cell, and the generation of IMP is reduced by downregulating the level of the AMPD3 by knocking down the AMPD3 gene so as to inhibit the death of the granulosa cell iron. Animal experiments prove that in a Dehydroepiandrosterone (DHEA) -induced PCOS mouse model, the ovarian tissue-specific knock-down of AMPD3 can reduce the death process of granulosa cell iron, remarkably improve ovarian function, endocrine disturbance and metabolic abnormality, restore estrus cycle, increase the number of sinus follicles and corpus luteum, and reduce the formation of saccular follicles. Based on the findings, the invention provides the following technical scheme: in a first aspect, the present invention provides the use of an AMPD3 gene expression inhibitor in the manufacture of a medicament for the prevention, alleviation and/or treatment of polycystic ovary syndrome. In some embodiments of the invention, the AMPD3 gene expression inhibitor is a nucleic acid molecule targeting the AMPD3 gene sequence, or a recombinant vector comprising said nucleic acid molecule. In some embodiments of the invention, the nucleic acid molecule is an siRNA or an shRNA, and/or the recombinant vector is a non-viral vector or a viral vector. In some embodiments of the invention, the targeting sequence of the shRNA is the nucleotide sequence shown in SEQ ID NO. 2. In some embodiments of the invention, the sense strand sequence of the shRNA is SEQ ID NO. 3 and the antisense strand sequence is SEQ ID NO. 4. In some embodiments of the invention, the patient suffering from the polycystic ovary syndrome has one or more of the following pathological features: An abnormal ovarian granulosa