PEDF based therapy for angiogenesis-related reproductive disorders

Technology

A novel anti-angiogenic based therapy using recombinant pigment epithelium-derived factor (PEDF)  for the treatment of angiogenesis related gynecological disorders such as ovarian hyperstimulation syndrome (OHSS), endometriosis, polycystic ovary syndrome (PCOS) and to improve egg quality.

PEDF is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic and anti-inflammatory activities that are partially mediated by negating VEGF activity. The anti-angiogenic effect of PEDF has been extensively investigated in the eye and in cancer, demonstrating its role in decreasing abnormal neovascularization. Growing amounts of evidence target VEGF as the main effector in the pathogenesis of angiogenesis-related gynecological disorders. We believe that utilizing our comprehensive knowledge of the role of PEDF in the reproductive system makes it a promising therapeutic agent for reproductive angiogenesis-related pathologies.

The Need

The current therapeutic armamentarium of OHSS, endometriosis and PCOS consists of symptomatic managing; there are no available drugs to cure these diseases.

OHSS is a complication of assisted reproduction techniques that causes the utmost concern. The incidence of OHSS is estimated to be around 6–12% of IVF treatments, with the severe cases that often require hospitalization being about 2–4%.

Endometriosis is a chronic and recurrent disease characterized by the presence and proliferation of functional endometrial cells outside the uterine cavity. Studies estimate that approximately 10–15% of all women of reproductive age are affected. Patients with endometriosis often suffer from pain as well as infertility, resulting in a severely limited quality of life and high-related healthcare costs.

PCOS is the most common endocrine disorder in women of reproductive age (about 7% - 10% of women worldwide). PCOS is associated with infertility. These women are at high risk for developing OHSS as a result of gonadotropin stimulation and are also more likely to develop endometrial cancer.

Po

tential Application

• Treatment of endometriosis

• Prevention and treatment of OHSS

• Treatment of PCOS

• Improvement of oocytes quality

Stage of Development

Following characterization of the physiological expression of PEDF in the reproductive organs and establishment of in vivo models for OHSS and endometriosis we demonstrated that:

• PEDF alleviates OHSS symptoms either as a preventive or therapeutic agent. 

• PEDF inhibits proliferation of endometriotic lesions in endometriosis.

• Subcutaneous administration of 2mg/kg PEDF was set as the preferable treatment regimen. 

• The role of PEDF in the pathogenesis of these syndromes and its mechanism of action is evolving.

• Preliminary safety studies demonstrated no effect on reproductive parameters.

Patents

Patent application (PCT/IL2010/000936) pending in US and Europe

Supporting Publications

1.         Chuderland, D., Ben-Ami, I., Ron-el, R., Grossman, H., Kaplan-Kraicer, R.., Satchi- Fainaro2, R, Eldar-Boock, A., and, Shalgi, R. (2012) Hormonal regulation of Pigment Epithelium Derived Factor (PEDF) in granulosa cells.  Mol. Hum. Reprod. Feb; 19 (2):72-81 2013.

2.         Chuderland, D., Ben-Ami, I., Kaplan-Kraicer, R., Grossman, H., Shalgi, R. (2012).  The role of pigment epithelium-derived factor in the pathophysiology and treatment of ovarian hyperstimulation syndrome in mice. J. Clin. Endocr. Metab. Feb; 98 (2): E258-66, 2013.

3.         Chuderland, D., Hasky, N., Ben-Ami, I., Kaplan-Kraicer, R., Grossman, H. Shalgi, R.  A physiological approach for treating endometriosis by recombinant pigment epithelium-derived factor (PEDF). Hum. Reprod. March 2013 PMID: 23466670.

4.         Chuderland, D., Ben-Ami, I., Fridler S., Hasky, N., Shalgi, R. Pigment epithelium derived factor (PEDF) is dynamically expressed in the endometrium. Under review, Hum. Reprod.

Project manager

Elisha Natan
Director BD

Project researchers

Ruth Shalgi
T.A.U Tel Aviv University, Medicine-Sackler Faculty
Cell and Developmental Biology

Raphael Ronel
,