Therapeutic strategies for the prevention and treatment of Congenital Cytomegalovirus Disease
Stuart Hamilton, BSc, PhD
BACKGROUND: Congenital cytomegalovirus (CMV) is the leading non-genetic cause of fetal malformation in developed countries. Congenital CMV causes lifelong clinical sequelae in children including mental disability, sensorineural hearing loss, vision loss, intrauterine growth restriction, microcephaly, motor defects and in severe cases causes fetal and neonatal death.
GAP: Fetal injury is caused by direct CMV cytopathic damage to the fetus following maternofetal transmission via the placenta or indirectly by dysregulating normal placental development and function. Despite the clinical and social importance of congenital CMV, there are currently no licensed therapeutics for use during pregnancy to prevent fetal injury primarily due to drug toxicity and limited evidence for therapeutic efficacy.
HYPOTHESIS: Inhibiting CMV replication in the placenta will reduce vertical transmission during pregnancy and prevent direct and indirect viral injury to the developing fetus. The in vitro correlates of new experimental in vivo anti-CMV therapeutics will be modeled in our established human placental models to provide urgently needed preclinical data for potential use during pregnancy.
METHODS: Human ex vivo placental explant histocultures and placental cell culture models will be utilized to examine the efficacy and safety profiles of experimental antivirals in response to CMV infection. A range of molecular biology techniques will be utilized including; qRT-PCR, plaque assay, western blot, immunofluorescence, immunohistochemistry, ELISA, and cytotoxicity/functional assays.
IMPACT: This investigation will provide invaluable preclinical data on the efficacy and safety profiles of experimental anti-CMV therapeutics to prevent and treat congenital CMV disease. The findings of this study will immediately influence future directions in therapeutics for CMV affected pregnancies and provide strong impact against one of the global leading causes of disability in the newborn.
Website Link: http://www.virologyresearch.unsw.edu.au
This work is partly supported by the Australian National Health and Medical Research Council (Hamilton – APP1127717).