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Jeff Fitlow/Rice University
Researchers have developed an adeno-associated virus (AAV) that releases its payload only in the presence of 2 selected proteases.
Because certain proteases are elevated at tumor sites, the virus can be designed to target and destroy cancer cells.
Junghae Suh, PhD, of Rice University in Houston, Texas, and her colleagues engineered the virus and described their work in ACS Nano.
AAVs have become the object of study as delivery vehicles for gene therapy.
Researchers often try to target AAVs to cellular receptors that may be slightly overexpressed on diseased cells, but Dr Suh’s team took a different approach.
“We were looking for other types of biomarkers beyond cellular receptors present at disease sites,” she 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.”
But when the programmed AAVs encounter the right proteases at sites of disease, they unlock and bind to the cells. The AAVs then deliver payloads that will either kill the cells, in the case of cancer therapy, or deliver genes that can repair the cells.
Dr Suh and her colleagues genetically insert 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 1 protease, it might be at the cancer site, but it could also be somewhere else in your body where you have inflammation,” Dr Suh said. “This could lead to undesirable side effects.”
“By requiring 2 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.”
The ultimate vision of this technology is to design viruses that can carry out a combination of steps for targeting.
“To increase the specificity of virus unlocking, you can imagine creating viruses that require many more keys to open,” Dr Suh said. “For example, you may need both proteases A and B, as well as a cellular receptor, to unlock the virus. The work reported here is a good first step toward this goal.” 
Jeff Fitlow/Rice University
Researchers have developed an adeno-associated virus (AAV) that releases its payload only in the presence of 2 selected proteases.
Because certain proteases are elevated at tumor sites, the virus can be designed to target and destroy cancer cells.
Junghae Suh, PhD, of Rice University in Houston, Texas, and her colleagues engineered the virus and described their work in ACS Nano.
AAVs have become the object of study as delivery vehicles for gene therapy.
Researchers often try to target AAVs to cellular receptors that may be slightly overexpressed on diseased cells, but Dr Suh’s team took a different approach.
“We were looking for other types of biomarkers beyond cellular receptors present at disease sites,” she 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.”
But when the programmed AAVs encounter the right proteases at sites of disease, they unlock and bind to the cells. The AAVs then deliver payloads that will either kill the cells, in the case of cancer therapy, or deliver genes that can repair the cells.
Dr Suh and her colleagues genetically insert 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 1 protease, it might be at the cancer site, but it could also be somewhere else in your body where you have inflammation,” Dr Suh said. “This could lead to undesirable side effects.”
“By requiring 2 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.”
The ultimate vision of this technology is to design viruses that can carry out a combination of steps for targeting.
“To increase the specificity of virus unlocking, you can imagine creating viruses that require many more keys to open,” Dr Suh said. “For example, you may need both proteases A and B, as well as a cellular receptor, to unlock the virus. The work reported here is a good first step toward this goal.”
Jeff Fitlow/Rice University
Researchers have developed an adeno-associated virus (AAV) that releases its payload only in the presence of 2 selected proteases.
Because certain proteases are elevated at tumor sites, the virus can be designed to target and destroy cancer cells.
Junghae Suh, PhD, of Rice University in Houston, Texas, and her colleagues engineered the virus and described their work in ACS Nano.
AAVs have become the object of study as delivery vehicles for gene therapy.
Researchers often try to target AAVs to cellular receptors that may be slightly overexpressed on diseased cells, but Dr Suh’s team took a different approach.
“We were looking for other types of biomarkers beyond cellular receptors present at disease sites,” she 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.”
But when the programmed AAVs encounter the right proteases at sites of disease, they unlock and bind to the cells. The AAVs then deliver payloads that will either kill the cells, in the case of cancer therapy, or deliver genes that can repair the cells.
Dr Suh and her colleagues genetically insert 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 1 protease, it might be at the cancer site, but it could also be somewhere else in your body where you have inflammation,” Dr Suh said. “This could lead to undesirable side effects.”
“By requiring 2 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.”
The ultimate vision of this technology is to design viruses that can carry out a combination of steps for targeting.
“To increase the specificity of virus unlocking, you can imagine creating viruses that require many more keys to open,” Dr Suh said. “For example, you may need both proteases A and B, as well as a cellular receptor, to unlock the virus. The work reported here is a good first step toward this goal.”