Key Points
- The Advanced Research Projects Agency for Health (ARPA-H) recently announced that it funded a new preclinical project seeking to slow age-related cognitive decline in women.
- In this project, researchers will use focused ultrasound together with a newly developed drug to improve the function of the brain’s lymphatic system.
The Advanced Research Projects Agency for Health (ARPA-H) recently announced funding awards for its Sprint for Women’s Health Program. Young-Kwon Hong, PhD, chief of the Division of Basic Science Research in the Department of Surgery at the University of Southern California (USC) Keck School of Medicine, has been awarded a $3.4 million grant to develop the synergistic use of focused ultrasound with new small compound agonists for the Piezo1 mechanosensor that he and his team discovered in the laboratory. The drug – which they call “Luke Skywalkers” in keeping with the tradition of naming Piezo1 agonists after iconic Star Wars characters such as Yoda1, Dooku1, and Jedi1/2 – improves the function of the brain’s lymphatic, or waste clearance, system. The idea for the project is to slow age-related cognitive decline in women by using focused ultrasound along with the drug in the area of the brain that controls the lymphatic system.
Dr. Hong and his team conduct research centered around the Piezo1 molecule, which is a protein that serves as an ion channel in cellular membranes and senses external forces. He says that because lymphatics provide a “sewer system” for the brain – and the cellular membranes of the lymphatic system are controlled by Piezo1 molecules – the lymphatic system senses high and abnormal levels of fluid accumulation. The team’s new drug affects the lymphatic system through Piezo1 activation, improving the way the system clears fluid and waste from the brain. Initially developed for the treatment of hydrocephalus and some symptoms of Down’s syndrome, the drug was found to increase the diameter of the lymphatic vessels and speed up the lymphatic system’s clearance rate. After it worked to clear extra fluid from the brain, Dr. Hong’s group began to theorize that the treatment might also work for diseases that cause cognitive decline, like dementia.
“Focused ultrasound is new to me and my lab members, but we are excited to use it along with our drug to stimulate the lymphatic system,” said Dr. Hong. “The recently identified nasopharyngeal lymphatic plexus, or NPLP, is the central hub of the brain’s lymphatic system, which clears waste from the brain. When we applied focused ultrasound to the NPLP in the presence of our drug, it improved lymphatic drainage to clear the brain of debris and toxins. We saw a dramatic synergy between the focused ultrasound and the chemicals. That’s because focused ultrasound opens up the Piezo1 channel, while the chemicals delay its closing process, together generating a profound synergistic efficacy.”
For the study funded by ARPA-H, Dr. Hong and his team will optimize the combination of focused ultrasound plus their drug in various preclinical models and then suggest parameters for translating the study into human clinical trials.
“Anyone with a loved one in cognitive decline knows how devastating—and terrifying—it can be for the patient and for everyone around them,” said Dr. Hong in the USC press release. “…Combining targeted ultrasound therapy with our drug therapy may offer hope…We may even be able to refine the treatment to a simple at-home process. This has an enormous potential to help people keep their dignity and their connection to loved ones.”
Each project funded by the ARPA-H Sprint for Women’s Health Program is listed on the awardee page.
See the Press Release from the Keck School of Medicine at USC
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