A human brain organoid model of acute prenatal hypoxia enables biomarker discovery and drug screening for hypoxic-ischemic encephalopathy

Project Summary

Hypoxic-ischemic encephalopathy (HIE), also known as birth asphyxia, occurs at a rate of 4/1000 live births. Strikingly up to 60% of HIE affected infants die or have severe disabilities by the age of 2 and intellectual/developmental disabilities later in life. Currently the only therapeutic option for HIE is hypothermia, and this needs to be started as soon as possible after birth when the precise level of damage to the neonatal brain from a prenatal hypoxic insult of unknown severity is difficult to quantify. Furthermore, the benefits of therapeutic hypothermia remain limited and often doesn’t prevent long-term impairments, highlighting the need for better early HIE diagnostics and therapeutics.

Because of fundamental differences between humans and animals in brain development and responses to hypoxia we have developed a human stem cell derived brain organoid model of HIE that mimics the acute hypoxic stress impacts on the perinatal brain. In this project we propose to leverage this innovative brain organoid model to: a) Dissect the temporally modulated molecular and cellular effects of different levels and lengths of hypoxia on the developing human brain at a single cell level b) Elucidate how the severity of HIE impacts subsequent brain development c) Identify novel human biomarkers that permit rapid stratification of HIE severity in neonates d) Test novel therapeutics for HIE and benchmark these against therapeutic hypothermia.

This program of work constitutes a step change in our understanding of the acute and long-term impacts of HIE on the human brain, enables the discovery of novel biomarkers that will allow neonatal physicians to better tailor treatments through improved patient stratification, and foster the development and testing of novel therapeutics at scale in a human relevant model with global health-economic impact.