Development of molecular target therapy for human implantation failure focusing on nuclear transcription factor activity

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Using transient in vivo gene transfer system into mouse uterus, we have successfully introduced stat-3 decoy double strand oligonucleotides or dominant negative stat-3 mutant cDNA into mouse pregnant uterine cavity on day 1.5 post coitum. This procedure with Haemagglutinating Visur of Japan (HVJ)-envelope vector did not disturb the physiological course of pregnancy. After disturbing stat-3 activation at the implantation window, we noticed implantation process was totally disturbed. Evans blue injection did not induce "blue bands" at the implantation sites. Hormonal milieu including progesterone was did not altered by this treatment. Moreover, disturbing stat-3 activity also inhibit decidualization after pseudo-pregnant and mechanical stimuli in the mouse uterus.Depending on these observations, we observed stat-3 activating status in human mid-lueal endometrium obtained by endometrial dating biopsy. Immunohistochemical staining using anti phosphor-stat-3 antibody indicated that, in endometrium from infertile patients underwent 2 or more cycles of morphologically healthy embryo transfer and fail to conceive, immunoreactivity of phosphor-stat-3 tended to be weak or undetectable. Further investigation should be required to clarify the relationship between stat-3 activation status and human implantation failure. Our data may provide the clue to understand the pathophysiology of implantation failure.