Organoid shows how COVID affects those with Down syndrome

Scientists at The University of Queensland (UQ) have developed a synthetic organoid that mirrors the brain of a person with Down syndrome to explore why people born with the genetic condition are more vulnerable to COVID-19 and identify therapies that will reduce its impact.

The work was led by Dr Mohammed Shaker and organoid Professor Ernst Wolvetang from UQ’s Australian Institute for Bioengineering and Nanotechnology (AIBN). Shaker explained that the risk of hospitalisation and death from coronavirus is much higher for people with Down syndrome, but until now there has been no clear data that explains why.

Seeking answers, the researchers turned to organoids — tiny, synthetic organ replicas grown from human stem cells that researchers use to carry out experiments that would be ethically and practically difficult in live subjects. They grew Down syndrome brain models and encased them in a layer of specialised cells known as the choroid plexus, effectively creating an organoid with two functional brain domains in what is understood to be a world first.

Testing on the new organoid models revealed that certain components of the choroid plexus are underdeveloped in people born with Down syndrome. As explained by Wolvetang, “The barrier function of the choroid plexus prevents coronavirus from infecting brain cells, and this barrier is compromised in people with Down syndrome.

“It means a crucial line of defence is missing and explains why patients in this cohort experience more severe COVID-19 symptoms.”

The lab then used the organoids to screen drug therapies that could compensate for this vulnerability, including the US FDA-approved drugs Avoralstat, Camostat, Nafamostat and Remdesivir. Their results were published in the journal Science Advances.

Shaker said it was clear that human brain organoid models could be important medical tools that offer unprecedented insights and potential drug screening for a range of conditions beyond Down syndrome and COVID-19, stating, “This work exemplifies how increasingly sophisticated human brain organoid models can be used to discover the cellular and molecular processes driving neurological diseases.

“It also shows that these organoids are crucial tools that allow us to evaluate the safety and efficacy of new therapeutics at scale.”

Image caption: The researchers enveloped Down syndrome brain models in a layer of specialised cells called the choroid plexus (pictured here with immunostaining).