Three researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have received awards to pursue treatments and vaccines for COVID-19 from the California Institute for Regenerative Medicine, the state’s stem cell agency.
The recipients are Dr. Gay Crooks, a professor of pathology and laboratory medicine and of pediatrics and co-director of the UCLA Broad Stem Cell Research Center and Dr. Christopher Seet, an assistant professor of hematology-oncology; and Dr. Brigitte Gomperts, a professor of pediatrics and pulmonary medicine.
Crooks and Seet's $150,000 award will support their study into how immune cells called T cells respond to SARS-CoV-2, the virus that causes COVID-19, in order to inform the development of vaccines and therapies that harness T cells to fight the virus.
The scientists are taking an innovative approach to vaccine research in that rather than studying the immune response using cells taken from infected people, they are taking T cells that have been donated by healthy people and inducing them to mount strong immune responses to parts of the virus in the lab. Studying the T cells' responses will shed light on how T cells recognize and eliminate the virus.
Their method uses blood-forming stem cells – which can self-renew and form all types of blood and immune cells – taken from healthy donors and infected with a virus containing parts of SARS-CoV-2. These stem cells are then converted into specialized immune cells called dendritic cells using a new method developed by Seet and Suwen Li, a graduate student in Crooks' lab. Both Seet and Li are graduates of the UCLA Broad Stem Cell Research Center's Training Program.
Dendritic cells are rare immune cells that devour proteins from foreign invaders–including viruses—and then chop them into fragments called antigens, which can then trigger T cells to mount an immune response to the virus.
"The dendritic cells we are able to make using this process are really good at chopping up the virus, and therefore eliciting a strong immune response," said Crooks, who is also director of the cancer and stem cell biology program at the UCLA Jonsson Comprehensive Cancer Center.
Rare T cells with receptors on their surfaces that can recognize these viral antigens as foreign and dangerous set off a chain of events that activates multiple parts of the immune system to attack cells infected with the virus. Protective responses by T cells against a virus also may result in long-lasting immune memory and protection from future infections with the same virus.
The work being done by Crooks and Seet will not only identify the receptors on T cells capable of recognizing SARS-CoV-2, but also determine which antigens of SARS-CoV-2 are the best at inducing strong T-cell immune responses. This information can then be used to guide development of vaccines for COVID-19 that result in stronger T-cell responses and better immune memory.
"What we know from a lot of work going on in other viral infections and also in cancer immunotherapy is that T-cell responses are really important for long-lasting immunity," Seet said. "And so this approach will allow us to better characterize the T-cell response to SARS-CoV-2 and focus vaccine and therapeutic development on those parts of the virus that induce strong T-cell immunity."
Gomperts' $150,000 award will support the use of a human stem cell-derived lung organoid model to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with SARS-CoV-2.
Over the past several years, Gomperts has been developing three-dimensional lung organoids that can serve as disease-in-a-dish models to yield unprecedented insights into lung diseases. The organoids are grown by coating tiny gel beads with human lung-derived stem cells and then allowing them to self-assemble into the shapes of the air sacs found in human lung.
"Our model resembles actual human lung tissue because it contains several of the lung cell types you would find in the body that are arranged into the micro-architecture of the lung," Gomperts, who is also a member of the UCLA Jonsson Comprehensive Cancer Center, said.
Most drug screens for SARS-CoV-2 lung therapies currently underway utilize two-dimensional cultures of lung cells, which fail to recreate many critical aspects of the organ's biology and response to disease. Because Gomperts' model more closely mimics the conditions inside the human lung, it should better predict how the lungs of patients with SARS-CoV-2 will respond to therapies.
Along with her collaborators from the department of molecular and medical pharmacology, Associate Professor Vaithilingaraja Arumugaswami and Professor Robert Damoiseaux, Gomperts will infect her lung models with SARS-CoV-2 to better understand the biology of the disease and screen thousands of drug candidates.
The group will begin by using the models to test drugs that have been approved by the Food and Drug Administration for other purposes or have been found to be safe in humans in a phase one clinical trial. This increases the likelihood that if a successful drug is found, it can be fast tracked for approval.
"We're starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible," Gomperts said.
Each award will be matched dollar-for-dollar by the UCLA Broad Stem Cell Research Center. Both of the projects awarded are based upon research that has previously received support from both CIRM and the UCLA Broad Stem Cell Research Center.
"Our center is proud to join CIRM in supporting these researchers as they adapt projects that have spent years in development to meet the urgent need for therapies and vaccines for COVID-19," said Dr. Owen Witte, founding director of the UCLA Broad Stem Cell Research Center and professor of microbiology, immunology and molecular genetics. "This moment highlights the importance of funding scientific research so that we may have the foundational knowledge to meet new challenges as they arise."
