Suff, Natalie; (2017) The use of cervical gene therapy for the prevention of infection-related preterm birth. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Approximately 40% of preterm births are preceded by microbial invasion of the intrauterine space, with ascent from the vagina being the most common pathway. Antimicrobial peptides (AMPs), in combination with mucin and other immune cells, constitute a barrier within the cervical canal which prevents ascending infection. I investigate whether overexpression of human beta-defensin 3 (HBD-3), a potent AMP, in the cervical mucosa prevents bacterial ascent from the vagina into the uterine cavity of pregnant mice. / Methods: Models of ascending infection and preterm birth: Mice received E.coli (non-pathogenic K12 or pathogenic K1 with integrated luxABCDE operon) intra-vaginally at E16.5 and bacterial ascension was monitored by live whole body bioluminescence imaging. / AAV gene therapy: An adeno-associated virus vector (AAV8) containing the HBD-3 transgene was synthesised (AAV8-HBD3). AAV8-HBD3 or control vector AAV8-GFP control was administered intravaginally into E13.5 pregnant mice. This was followed by induction of ascending infection at E16.5 as described above. / Results: Following vaginal infection with E.coli K12, bioluminescence imaging showed bacterial ascent into the uterine cavity but this did not lead to preterm birth. Following vaginal infection with E.coli K1, bioluminescence showed bacterial ascent into the uterine cavity leading to subsequent premature delivery and a reduction in pups born alive, compared with uninfected controls. Following intravaginal infection with E.coli K12 or K1, there was significantly less uterine bioluminescence in the AAV8-HBD3 treated mice at 24 and 48 hours after infection compared with the AAV8-GFP controls, signifying reduced uterine bacterial ascent in the AAV8-HBD3 treated mice. Although there was no increase in the gestation length in the E.coli K1 dams following AAV8-HBD3 treatment, there was an increase in the proportion of live pups at delivery compared with AAV8-GFP controls. / Conclusion: AAV-HBD3 may be a promising candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth.

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