Lung Organoids: Mini-Models for Mega Answers

Like other viruses, COVID-19 could be treated with an antiviral drug. Unlike other viruses, there is no known antiviral that specifically treats this virus. Senior Investigator Melanie Ott, MD, PhD, wants to change that.

While most antivirals target the viral proteins themselves, Ott is looking for antiviral drugs that target host proteins. These antivirals would “starve” the virus from the host resources that allow it to reproduce. Moreover, there is a better chance of long-lasting effectiveness if the antiviral targets host proteins as they mutate at a slower rate than viral proteins. To get closer to finding the antiviral effective against COVID-19, Ott and her team are testing drugs in primary lung models including lung organoids, three-dimensional tissue cultures that replicate the features of the larger organ.

By using primary lung models for screening potential treatments, the team increases the chance that their discoveries will translate to therapies that will be effective in people. Although much smaller, a lung organoid resembles the functions and features of the actual organ. “With our collaborators, we grow organoids either from iPSCs or from the stem cells of the full-size organ, and because they are closer to the real thing, we get a better picture of how lungs react to different treatments,” explains Ott.

The therapeutic approach Ott’s team is pursuing—targeting the host proteins rather than the virus to stem infection—is one she and Nevan Krogan, PhD, have prioritized for a while. While the SARS-CoV-2 virus appears to mutate at a slower rate than other viruses, for instance HIV, human cells mutate even slower. Any antiviral developed based on the viral proteins would quickly become irrelevant by the rapid mutation of the virus. An antiviral against the host proteins will last longer, and also has the potential to be repurposed for other viruses.

Ott’s team takes advantage of a comprehensive map of the interactions between the virus and host proteins. This map was generated by a team of researchers led by Nevan Krogan, who has previously created similar maps for other viruses like HIV and Zika. With the map in hand, Krogan, Ott and their colleagues have already identified host proteins to target and prioritized FDA-approved or pending approval drugs that should be screened for potential antiviral effectiveness.

Now Ott’s team is prepared to use the lung organoids and other lung models to screen these drugs and others, as new candidates arise from additional studies of host and virus interactions.

The two approaches to finding effective drug therapies taken by the Gladstone team are powerful on their own. The focus on screening FDA-approved drugs avoids the lengthy approval process. Using lung organoids to screen potential therapies bypasses simpler screening methods saving time in identifying effective treatments. By combining these approaches, Ott’s team hopes to create a faster pipeline to usable drugs.