Robert M. Berne Cardiovascular Research Center Resident Member and Frances Myers Ball Endowed Professor of Medicine, & Cardiovascular Division Vice-Chief for Research, Jonathan Lindner, MD, was recently awarded a $2,869,442 grant from the NIH’s National Heart, Lung, and Blood Institute (NHLBI) to study how ultrasound can be used to improve gene therapy delivery. Dr. Lindner is the vice chair of the NHLBI’s Data and Safety Monitoring Board for Gene and Cell Therapies, and in that role reviewed many studies using adeno-associated viruses (AAVs) to deliver gene therapies to cardiac tissues. AAVs are genetically modified viruses that infect human cells without causing disease. Many of the studies reviewed and monitored by the Committee indicated that the doses of AAV required to be effective at reversing cardiac diseases were also unsafe due to life threatening inflammatory reactions. Lower doses that are safe are much less effective, indicating a need to safely amplify AAV delivery only to target tissues.
Dr. Lindner has experience in ultrasound-mediated drug and gene delivery. One of his first projects at UVA was a collaboration with Dr. Brent French, PhD, using ultrasound to deliver DNA for gene therapies. Now, 16 years later, Dr. Lindner and French are again working together on gene therapy delivery. Dr. Linder’s team specializes in ultrasound therapies and French’s team has deep expertise in AAV design.
“Sitting on the NHLBI data safety monitoring board made me see that there was a major gap in gene therapy. I thought that the ultrasound stimulation (cavitation) of microbubbles that are conventionally used as ultrasound contrast agents have the potential to markedly increase macromolecule transfer from the vascular compartment to tissues. The whole thing about gene therapy is you need to get enough gene in the right place in a site-specific manner in a safe process,” Dr. Lindner explained. To reduce the amount of AAV needed, Dr. Lindner is using ultrasound to help the viral particles diffuse out of blood vessels. The process involves injecting encapsulated bubbles smaller than the size of red blood cells into a vein, then exposing the target tissue to ultrasound with specific acoustic conditions. The ultrasound waves cause the bubbles to oscillate, which allows the AAVs to more efficiently exit the vascular space through a variety of different mechanisms, which Dr. Lindner is studying in the NIH-funded research.
“We use non-invasive, standard ultrasound and can probably also use conventional microbubble contrast agents which are already approved for human use, which will facilitate transitioning this technology to the patients. This project will establish the efficacy and safety of the procedure using mouse and primate studies, and we will attempt to reverse a genetic heart disease in mice that mimics one of the most common genetic cardiac conditions in humans The people and resources of the CVRC have been essential to Dr. Lindner’s work. “The CVRC has just such great diversity of talent. This project requires a wide diversity of talent. We are so lucky to have a community of talented researchers who not only have the right skills, but also the right attitude to work together as a successful team.”