SHAKER LIFE | WINTER 2017 49 A Sheep in Wolf’s Clothing This makes HIV a poor door-to-door salesman of viruses: Its host cell customers readily open their doors to get the sales pitch, but that pitch doesn’t always convert into a sale. In isolation, this makes HIV infection appear unlikely. But inside a human being, there’s a Roman army of these salesmen, making HIV a volume business with catastrophic results. So Tilton began to look at HIV in a different way, wondering if he could make HIV a sheep in wolf’s clothing. He considered the possibility of modifying HIV particles enough so that they could get a diseased cell to open its doors, which by itself is enough to deliver highly specific, helpful proteins that could have positive effects on the cell – no sales pitch required. This brand of medicine, called protein therapeutics, uses naturally occurring or modified proteins that bind to a receptor on the surface of a damaged cell to initiate a reaction that’s beneficial to a patient. The difference for Tilton is that he wants to find a way to deliver a protein inside the cell. Enter Tilton’s nanoPODs (short for nanoscale protein delivery), strategically engineered non-infectious HIV particles that sense intracellular environments and then set off a chain of events based on that environment. Tilton and his team have used nanoPODs in vitro to determine whether a cell is infected with HIV. He’s found that uninfected cells are unchanged. The story for HIV-infected cells is less rosy. The nanoPOD sets off a reaction inside the cell which results in apoptosis, or cellular suicide. “We can probe whether HIV is in a cell and then specifically kill cells that are HIV-infected and not kill healthy cells,” he says. Down the road, Tilton is hoping to find a way to use nanoPODS loaded with therapeutic proteins to replace defective proteins, or, in the case of cancer, to eliminate pre-cancerous cells and stop the disease before it even becomes apparent. “Most small molecule drugs – the drugs we take in pill form – are well absorbed, but tend to go all over the body, so that’s where a lot of the side effects come from,” Tilton says. “In contrast, our nanoPODs can potentially deliver protein therapeutics very selectively to target cells and have sophisticated actions that reduce side effects and add whole new classes of function.” A Glimmer of Hope Even more fascinating (and bordering on science fiction) is the possibility in genome editing. Recently, Tilton and his colleagues at Case used a nanoPOD to deliver both a protein and RNA inside a cell. For those with inborn errors of metabolism (genetic errors where the body can’t convert food to energy), this discovery provides a glimmer of hope. “Our goal would be to go in and fix their genome so that it encodes a functional gene. We would try to get the particles to deliver enough of these gene editing proteins to go in and fix the damaged cells,” he explains. Tilton emphasizes that his work is still very much exploratory. “If we can deliver proteins into cells in vivo in a living organism, then we’ll basically have leapfrogged a majority of the protein delivery platforms out there and we’ll have been able to do something they haven’t been able to do.” That possibility and its potential keep Tilton motivated in a field that’s plagued with one step back for every two steps forward. “I can’t even see the stuff that I work with. It’s all too small. All I can do is measure and learn whether I’ve had an effect on the cell,” he says. One day, with a little luck and lots of persistence, Tilton just may cause the effect he’s been anticipating. And if it does, his place in the world of medicine just might be one for the books. SL
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