Labs Developing Viruses to Help Damaged Hearts

Rice bioengineer Junghae Suh wins NIH grant to lead gene therapy team

gene therapy
Junghae Suh

Rice University bioengineer Junghae Suh and colleagues at three partner institutions will lead a study that aims to fix damaged hearts with therapeutic genes delivered by viruses.

Suh has received a prestigious R01 grant for $2 million from the National Institutes of Health’s National Heart, Lung and Blood Institute to test adeno-associated viral vectors (AAVs) developed by her lab at Rice’s BioScience Research Collaborative to deliver therapeutic genes to sites of heart damage.

Along the way, a lab led by Eva Sevick at the University of Texas Health Science Center in Houston will use molecular imaging to study the in vivo delivery performance of the engineered AAVs, Mavis Agbandje-McKenna at the University of Florida will solve the structures of the vectors, and Walter Koch and Rajan Sudarsan and their team at Temple University will test the therapeutic potential of the gene therapy vectors.

The goal is a virus that can carry therapeutic transgenes to damaged heart tissue to turn cells that make up electrically insulating scar tissue into conductive – and therefore, beating – heart muscle cells known as cardiomyocytes.

AAVs have been a focus of Suh’s Synthetic Virology Laboratory for years. AAVs are benign virus capsids, or shells, about 25 nanometers across that are designed to deliver cargoes like strands of DNA that to cells. The viruses can be enhanced to target specific cells.

“We think of ourselves as the delivery truck lab,” said Suh, an associate professor of bioengineering. “What goes into the truck depends on the customer.”

These AAVs will be configured to target and be activated by matrix metalloproteinases known to be elevated in the extracellular matrix of damaged cardiac tissue after a heart attack. That will achieve three additional goals: A reduction of invasive surgery, a reduction of side effects from delivery to off-target organs and a reduction of dose-dependent immune responses to the AAVs.

“This therapy is mainly to treat the heart failure that’s associated with the progression of heart disease,” she said. “After a person has a heart attack, the damaged part of the heart never truly heals,” Suh said. “Patients end up getting a scar in that part of the heart and there are no therapies to reverse that scar back into healthy tissue. That’s been the focus of a lot of research, and it’s what we’re going after with gene therapy. We’re not interested in treating the symptoms; we’re interested in treating the underlying cause.

“We are trying to coax those cells back to health,” she said. “It’s unclear if it’s going to work the way we imagine, but we have to try. We’re talking about in situ regeneration of tissue. That is the dream.”

Suh said the Temple lab already has a therapeutic transgene to pair with her AAVs for testing in mouse models. She is also collaborating with other cardiovascular researchers. “They all have their own favorite transgenes they want to test out with the vector,” she said. “They have different hypotheses for why their transgene may be the best one.”

Having succeeded in proof-of-concept experiments, Suh said her lab is now working to optimize the viruses. “We want them to be more specific, more efficient, or both, depending on what’s needed to deliver the right kind of transgene,” she said. “It’s taken us a long time to get here, but it still feels like we’re just starting.”

Source : Rice University