Hristova, M. | bioRxiv Science

bioRxiv2023

Ascending vaginal infection in mice induces preterm birth and neonatal morbidity

Preterm birth (PTB; delivery <37 weeks), the main cause of neonatal death worldwide, can lead to adverse neurodevelopmental outcomes, as well as lung and gut pathology. PTB is commonly associated with ascending vaginal infection. Previously, we have shown that ascending E. coli infection in pregnant mice induces PTB and reduces pup survival. Here, we demonstrate that this model recapitulates the pathology observed in human preterm neonates, namely neuroinflammation, lung injury and gut inflammation. In neonatal brains, there is widespread cell death, microglial activation, astrogliosis and reduced neuronal density. We also validate the utility of this model by assessing efficacy of maternal cervical gene therapy with an adeno-associated viral vector containing human beta defensin 3; this improves pup survival and reduces Tnf mRNA expression in perinatal pup brains exposed to E. coli. This model provides a unique opportunity to evaluate the therapeutic benefit of preterm labour interventions on perinatal pathology.

neuroscience↗

bioRxiv2018

Gene therapy in argininosuccinic aciduria

Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathways via a single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.

genetics↗