Therapeutic Effect of Angiostatin Gene Transfer in a Murine Model of Endometriosis

Abstract

Endometriosis, the growth of ectopic endometrial tissue, is a chronic recurrent disease affecting 10% of the female population causing dyspareunia, pelvic pain, dysmenorrhea, and infertility. Suppression of ovarian activity is the cornerstone of medical therapy with limited benefit and severe adverse effects. Angiogenesis plays a major role in the development of endometriosis suggesting that anti-angiogenic therapy would offer a new therapeutic approach. We report successful treatment of endometriosis in estrogen-supplemented ovariectomized mice by transient overexpression (6 to 10 days of duration) of the gene for a natural angiogenesis inhibitor angiostatin, delivered to the peritoneum by a replication-deficient adenovirus vector (AdAngiostatin). Established endometriosis was eradicated in 14 of 14 AdAngiostatintreated animals, whereas 11 of 13 control animals showed full disease development. Administered to normal cycling mice for the same transient period, AdAngiostatin caused impaired ovarian function with suppressed corpus luteum development, decreased production of estradiol and progesterone, decreased ovarian and uterine weight, and increased body weight. AdAngiostatin treatment lowered the levels of sex steroids but did not induce total castration. Gene therapy with angiogenic inhibitors is a highly effective treatment for endometriosis, even in a host with preserved estrogen levels. However, local or targeted delivery of the gene must be considered to avoid prolonged systemic effects and impaired ovarian function. Endometriosis, the growth of functional endometrial tissue containing both glands and stroma outside the uterine cavity, is a chronic recurrent disease affecting a large number of women. Classic symptoms of endometriosis are dyspareunia, chronic pelvic pain, dysmenorrhea, and infertility. Affected women often have a poor quality of life and the disease is associated with significant health costs.1 Approximately 10% of the general female population suffer from endometriosis 2 and almost 70% of young women with chronic pelvic pain have the disorder.3 Among infertile women, the prevalence of endometriosis is 20 to 40% and presence of endometriosis decreases the success rate of in vitro fertilization. 4 Moreover, there is an association between untreated endometriosis and development of ovarian cancer.

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ c null immunodeficient mice

“…It therefore is conceivable that, in addition to the peritoneal environment (29), the angiogenic potential of the endometrial endothelial cells per se may be one of the critical determinants for the establishment and development of the endometriotic lesion. Antiangiogenic therapy recently has been proposed as an alternative treatment for endometriosis (23,30). This therapeutic strategy might be strengthened further by targeting endometrium-or endometriosis-specific angiogenesis, as postulated here.…”

Endometriosis and the neoplastic process

“…Soluble truncated receptor (Flt-1) and an affinity-purified antibody to human VEGF-A, significantly inhibited the growth of endometrial explants in a mouse in vivo model of endometriosis by disrupting the vascular supply. Gene transfection (using a replication-deficient adenovirus vector AdAngiostatin) of the endogenous angiogenesis inhibitor angiostatin to the peritoneum of a mouse was successful in treating a mouse in vivo model of endometriosis (Dabrosin et al 2002).…”

Distinct Roles for the α and β Subunits in the Functions of Integrin αMβ2

“…Refs. [15][16][17]. iC3b and Fg are two particularly important ligands of ␣ M ␤ 2 in mediating the inflammatory response to invasive agents or foreign materials (18 -20).…”