New use of fingolimod (GilenyaTM) to treat infection-sensitized neonatal hypoxic-ischemic encephalopathy (HIE) via inhibition of Sphingosine-1-Phosphate receptor (S1PR) activation.
- Has been shown to reduce inflammatory markers and brain loss in rat models of infection-sensitized hypoxia ischemia.
- Could be used to treat infection-sensitized neonatal encephalopathy, a condition with an unmet need.
- Is FDA approved to treat multiple sclerosis which potentially reduces regulatory hurdles.
In the developed world, the incidence of severe perinatal asphyxia leading to neurological impairment or death is roughly 1/1000 live births. This rate rises dramatically to ~1/100 live births however when only the developing world is considered. Further, infection of the fetal membranes due to bacterial infection (chorioamnionitis) is relatively common at ~14% of births in the US. When taken together, the prevalence of perinatal asphyxia and chorioamnionitis indicate that infection-sensitized neonatal HIE is a major health concern. Currently there are no therapies on the market and few in development to treat this condition.
Hypoxic-ischemic encephalopathy (HIE) arises when there is a lack of oxygen to the brain caused by almost any reduction in blood flow. Morbidities associated with this condition include intellectual disabilities, seizures and cerebral palsy. One of the subsets of this condition is neonatal HIE. Blood flow can be reduced for a number of reasons before, during and after birth; but, infection of the amnion (chorioamnionitis) has been repeatedly correlated with an increased severity in HIE. This situation is called infection-sensitized HIE. Emory inventors have discovered that S1PR is a key component of mediating the inflammatory response involved in infection-sensitized HIE. Antagonizing the S1PR with fingolimod was shown to reduce brain loss in a rat pup lipopolysaccharide model of inflammation where blood flow was reduced to the brain via carotid ligation. Additionally, inflammatory markers such as microglial activation and NF-ÎºB, were significantly reduced. The reduced brain atrophy and inflammation exhibited in rat pups treated with fingolimod suggest that the compound can be used to reduce morbidity in neonatal infection-sensitized HIE.