Activation of Brain Lymphatic Drainage Through Piezo1-Controlled Mechanotransduction as a Novel Hydrocephalus Therapy
Abstract
Hydrocephalus, also called water in the brain, is an abnormal accumulation of fluids in the brain, which causes headaches, weakness, problems balancing and walking, vision difficulties, memory loss, or even death when left untreated. Head injury, bleeding in the brain, infections, and brain cancers are a few causes of hydrocephalus. Current treatment for patients with hydrocephalus is the surgical insertion of a tube (shunt) as a bypass that can drain this fluid to other parts of the body. Although this surgical treatment has been performed for decades, the shunts get blocked and break down over time, requiring additional invasive surgeries. Although ~40,000 shunts are surgically placed in the brain annually in the United States, these types of surgeries are costly procedures with significant morbidities. Considering all these complications, it is critical to develop new treatment options that can effectively treat patients with hydrocephalus. The cerebrospinal fluid (CSF) in the brain is crucial for removing the brain waste products into the bloodstream. The lymphatic system has a network of vessels to drain fluid from tissues and back into the blood system. The brain has long been thought to be devoid of the lymphatic system. However, the brain lymphatic system was newly discovered. Since then, studies showed that the brain lymphatic system is responsible for the CSF fluid drainage from the brain and, by doing so, dispose of the brain cellular and metabolic wastes. Recently, our studies uncovered that a small molecule, Yoda1, can increase lymphatic drainage of the CSF. Yoda1 is a compound that activates a protein called Piezo1 residing on the surface of lymphatic cells. Piezo1 is a newly identified receptor that senses any physical forces applied to the cells, including fluid flow. The key finding is that Yoda1 is capable of activating Piezo1 in the absence of physical force. We exploited this principle and took advantage of Yoda1 as a Piezo1 activator in lymphatic cells, stimulating the lymphatic function. Indeed, we found that Yoda1 could enhance the lymphatic drainage of the CSF and thus effectively prevent brain swelling in animal models of hydrocephalus. However, Yoda1 turned out to be a poor drug candidate because it is metabolically instable and rapidly decayed in water. Thus, we initiated an extensive screening program and identified two Yoda1-like molecules with better medicinal properties and comparable therapeutic efficacies. The goal of this proposal is to test these two new molecules in rodents and large animals. Specifically, we will implement a human hydrocephalus-like injury in mice, rats, ferrets, and sheep. We will then treat these animal models with our new compounds and evaluate their efficacies, toxicities, and all drug-like properties. Our research group is an outstanding multidisciplinary team consisting of lymphatic biologists, pharmaceutical scientists, biomedical engineers, neurosurgeons, neuroscientists, animal geneticists, molecular biologists, neuroradiologists, brain-imaging specialists, and biostatisticians. If successful, we will have a novel drug for both active-duty warfighters sustaining brain trauma on the battlefields and the war Veterans who developed chronic hydrocephalus long after head injuries experienced during military service. After this proposal, we will be in a position to advance Yoda1 into an Investigational New Drug (IND)-enabling studies and set the stage for human testing. We believe that our experimental evidence of the effectiveness of two new molecules against hydrocephalus deserves thorough testing to determine the promise of this discovery. With the support of this proposal, we are confident that the project can be rapidly advanced into human studies. This approach is a much-needed therapeutic for patients who currently have limited treatment options. The ability to effectively treat hydrocephalus can improve the chance of regaining normal life for our Warfigh
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310822
Entities
People
- Young-kwon Hong
Organizations
- United States Army
- University of Southern California