Title: Cervical gene delivery of antimicrobial peptides for the prevention of infection-related preterm birth and subsequent neonatal brain injury
Funder: Action Medical Research

Abstract: Background_x000D_ Each year over 61,000 babies in the UK are born prematurely and sadly, more than 1,000 die as a result of being born too soon. Children who survive preterm birth, particularly those born before 32 weeks of pregnancy, have an increased risk of serious disabilities including cerebral palsy, visual impairment, hearing loss and learning difficulties. Infection is believed to be an important risk factor for preterm birth. Bacteria, commonly found in the vagina, are sometimes able to pass through the cervix and into the pregnant womb causing inflammation and triggering early labour. In addition, there is evidence that exposure to infection before birth damages the brain of the developing baby. This means that these babies are exposed to two possible causes of neurological damage - premature birth and infection-related brain injury._x000D_ Cells in the cervix produce specialised natural antimicrobial proteins that kill bacteria. These researchers plan to use gene therapy to boost levels of natural antimicrobial proteins at the cervix to see if this can prevent bacterial damage to the developing brain. _x000D_ _x000D_ The research project_x000D_ The first part of the study will involve looking more closely at the extent of neuroinflammation and fetal brain injury caused by different bacteria in a pregnant mouse model. The researchers will then use local gene therapy to increase production of an antimicrobial protein called HBD3 by the cervix. They will compare the pregnancy outcomes of mice that did or did not receive gene therapy, looking to see if HBD3 prevented bacteria from entering the uterus, if premature delivery occurred and comparing neurological assessments of the offspring at seven weeks. In the final part of the study, they will again use gene therapy to compare effects of HBD3 and another antimicrobial peptide, alone or in combination, on pregnancy outcome in their mouse model. The aims of this research are to show whether this gene therapy can prevent bacterial damage to the developing brain and also to help establish if the treatment is safe for both mother and baby. Ultimately, this work could lead to the development of a much needed new treatment to prevent preterm birth. In addition, if the treatment is shown to prevent infection-related brain injury, this would further support the long-term aim of reducing the number of babies born with permanent brain injury as a result of preterm delivery._x000D_ _x000D_ Action Medical Research and Borne are jointly funding this research._x000D_ _x000D_

Lay abstract: Background_x000D_ Each year over 61,000 babies in the UK are born prematurely and sadly, more than 1,000 die as a result of being born too soon. Children who survive preterm birth, particularly those born before 32 weeks of pregnancy, have an increased risk of serious disabilities including cerebral palsy, visual impairment, hearing loss and learning difficulties. Infection is believed to be an important risk factor for preterm birth. Bacteria, commonly found in the vagina, are sometimes able to pass through the cervix and into the pregnant womb causing inflammation and triggering early labour. In addition, there is evidence that exposure to infection before birth damages the brain of the developing baby. This means that these babies are exposed to two possible causes of neurological damage - premature birth and infection-related brain injury._x000D_ Cells in the cervix produce specialised natural antimicrobial proteins that kill bacteria. These researchers plan to use gene therapy to boost levels of natural antimicrobial proteins at the cervix to see if this can prevent bacterial damage to the developing brain. _x000D_ _x000D_ The research project_x000D_ The first part of the study will involve looking more closely at the extent of neuroinflammation and fetal brain injury caused by different bacteria in a pregnant mouse model. The researchers will then use local gene therapy to increase production of an antimicrobial protein called HBD3 by the cervix. They will compare the pregnancy outcomes of mice that did or did not receive gene therapy, looking to see if HBD3 prevented bacteria from entering the uterus, if premature delivery occurred and comparing neurological assessments of the offspring at seven weeks. In the final part of the study, they will again use gene therapy to compare effects of HBD3 and another antimicrobial peptide, alone or in combination, on pregnancy outcome in their mouse model. The aims of this research are to show whether this gene therapy can prevent bacterial damage to the developing brain and also to help establish if the treatment is safe for both mother and baby. Ultimately, this work could lead to the development of a much needed new treatment to prevent preterm birth. In addition, if the treatment is shown to prevent infection-related brain injury, this would further support the long-term aim of reducing the number of babies born with permanent brain injury as a result of preterm delivery._x000D_ _x000D_ Action Medical Research and Borne are jointly funding this research._x000D_ _x000D_

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;NEUROLOGICAL