US scientists have tinkered with a virus so that it opens its cargo doors only in the presence of certain enzymes that could be used to drop therapeutics precisely onto a target.
Scientists at Rice University described how they included small ‘peptide locks’ into the capsid of a virus, effectively locking it. In the locked state, the virus cannot deliver genetically encoded therapies. However, when the virus comes into contact with certain proteases, enzymes that cut up other proteins, the locks are chewed, releasing the therapeutic cargo inside.
“Our delivery platform seeks out elevated levels of extracellular proteases that are present in certain diseases, such as cancer and several neurological diseases. Upon detection of the proteases, the viral vectors ‘switch on’ and deliver nucleic acid cargo into cells,” explained Junghae Suh, lead author of the study and bioengineer at Rice University, Texas.
The cargo-door locks can be configured so that two specific proteases needed to open them. “By swapping out the amino acid sequence of the peptide locks, we can easily change what protease is recognized by our virus,” Suh told Biopharma-Reporter.com. A big advance was the fact that two different proteases are required for gene delivery, which will help make delivery tunable and predictable.
The paper is described as a proof-of-concept study, as a model transgene coding for green fluorescent protein was the payload (ACS Nano, DOI: 10.1021/nn500550q). In future studies, the researchers plan to deliver therapeutically relevant genes, depending on the biomedical applications. The group is now testing the viruses on various animal models.
Nucleic Acids delivery
The technology would deliver nucleic acids, so either genes or RNAi, as therapeutic models. The virus in the study was an adeno-associated virus, which is a benign virus often studied for gene therapy delivery. These viruses are often targeted to cellular receptors that may be slightly overexpressed on diseased cells.
Suh noted that elevated proteases are found around many diseased tissues. She believes that these protease-activatable viruses may be useful for the treatment of not only cancers but also neurological diseases, such as stroke, Parkinson’s and Alzheimer’s diseases, and heart diseases, including myocardial infarction and congestive heart failure.
“We are still in the early phases of our technology development. We did, however, recently submit a patent application on our platform,” she said.
"Gene therapy has been building increasing momentum over the past 5 years, with a growing number of successes in human clinical trials. A number of these successes have been made possible by gene delivery vehicles based on a harmless virus, adeno-associated virus (AAV)." commented David Schaffer, biomedical engineer at the University of California at Berkeley.
"There are, however, still a number of challenges in the development of gene delivery vehicles for more efficient and targeted delivery to specific cells and tissues. The authors have developed a promising strategy for targeted AAV gene delivery with potential applications for cancer."