Viruses cause many diseases but can also serve as vectors for delivery of genetic cargo for therapeutic purposes. Rice University researchers have now modified the adeno-associated virus, commonly used to deliver gene therapy, to work like a lock box that opens itself up only in the presence of two different chemical “keys”.
The virus responds to proteases, enzymes that break down other proteins, opening up and releasing the cargo only when both of the markers are present. By selecting which proteases unlock the virus, a new form of therapy may develop that allows doctors to precisely tune where gene delivery happens.
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“We were looking for other types of biomarkers beyond cellular receptors present at disease sites,” [Junghae Suh, bioengineer at Rice] said. “In breast cancer, for example, it’s known the tumor cells oversecrete extracellular proteases, but perhaps more important are the infiltrating immune cells that migrate into the tumor microenvironment and start dumping out a whole bunch of proteases as well.
“So that’s what we’re going after to do targeted delivery. Our basic idea is to create viruses that, in the locked configuration, can’t do anything. They’re inert,” she said. When programmed AAVs encounter the right protease keys at sites of disease, “these viruses unlock, bind to the cells and deliver payloads that will either kill the cells for cancer therapy or deliver genes that can fix them for other disease applications.”
Suh’s lab genetically inserts peptides into the self-assembling AAVs to lock the capsids, the hard shells that protect genes contained within. The target proteases recognize the peptides “and chew off the locks,” effectively unlocking the virus and allowing it to bind to the diseased cells.
“If we were just looking for one protease, it might be at the cancer site, but it could also be somewhere else in your body where you have inflammation. This could lead to undesirable side effects,” she said. “By requiring two different proteases – let’s say protease A and protease B – to open the locked virus, we may achieve higher delivery specificity since the chance of having both proteases elevated at a site becomes smaller.”
In the future, molecular-imaging approaches will be used to detect both the identity and concentration of elevated proteases. “With that information, we would be able to pick a virus device from our panel of engineered variants that has the right properties to target that disease site. That’s where we want to go,” she said.
Study in ACS Nano: Tunable Protease-Activatable Virus Nanonodes…