Using hiPSC-derived lung organoids, a clinically-relevant system, to validate & winnow a list of approved drugs that inhibit SARS-CoV-2 cytopathy

Using stem cells derived from actual patients, we have created "mini-lungs"-in-a-dish to understand how SARS-CoV-2, the virus that causes COVID, enters cells & causes disease. Our goal was to find drugs to block that process. Because the stem cells come from men & woman from a range of racial groups, we hoped to learn why some groups are more prone to worse COVID than others, reasoning that we might improve drug therapies for more susceptible groups. We learned that the virus can enter all lung cells not only through the "front door" we know about, but also through a "back-door" route. We identified a drug that could block that entry ("Apilimod"). We learned that the lung has its own heretofore unknown viral inflammatory/immune defense system controlled by a macromolecule called "surfactant" that previously was thought only to make lung air sacs pliable; surfactant does much more. Surfactant might diminish with aging, perhaps explaining why the elderly are more susceptible to COVID. We showed that adding surfactant (or its components) can augment the lung's intrinsic defense system & suppress infection & cell death. Both Apilimod & surfactant already FDA-approved & could be repurposed to help fight the most resistant or virulent cases of COVID. Our next steps will be to try to move approval of these drugs through the regulatory pathway to make them available to patients.