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Aptamers and siRNA

Aptamers and siRNA

The merging of two discoveries may provide a novel way to deliver cell destruction to prostate cancer. At the center of the research are two things familiar only to scientists—aptamers and small interfering RNA (siRNA). Aptamers are small molecules that work much like antibodies to target things—like cancer—that don’t belong in our bodies. They are really good at binding to other molecules. Prostate cancer expert Shawn Lupold developed an aptamer that targets the prostate-specific membrane antigen (PSMA), a protein found in most prostate cancer cells. Aptamers aren’t designed to have a particular shape or binding site for a target protein. Instead, they are selected from a pool of billions of different molecules by a stringent and complex process. When Lupold first took on the project as a graduate student, it took him five years to drill down to just the right chemical formulation.

Today, this can be chemically synthesized in just a few days. At the same time Lupold was working on his aptamer, Theodore DeWeese, Director of Radiation Oncology and Molecular Radiation Sciences, was working on another technology called siRNA that have the ability to turn off genes. Radiation therapy kills cancer cells by damaging their DNA. Some cancer cells, however, are able to repair the damage and survive, so DeWeese’s plan was to use siRNA to turn off genes that help perform these repairs.

Lupold’s aptamer allows him to do it selectively, causing harm only to cancer cells. Lupold’s prostate cancer-targeted aptamer was the perfect delivery vehicle for DeWeese’s radiation-sensitizing siRNA. Their final product was an aptamer that used PSMA as a chemical GPS system to guide the siRNA to prostate cancer cells, where they block DNA repair mechanisms, making prostate cancer cells ultrasensitive to radiation therapy. “It’s almost as if we turned up the radiation, but we did it molecularly,” says Lupold. Actually increasing the dose of radiation therapy would surely kill more cancer cells but be far too toxic to normal cells. This approach has the same effect, but it has the potential to do it more safely.

Their treatment worked well in animal models, and aptamers are already FDA approved for other medical purposes, so Lupold and DeWeese do not anticipate any safety problems. To move the therapy to clinical trials, they will need about $1 million to outsource the production of clinical-grade aptamers and to evaluate them in FDA-relevant preclinical models. DeWeese says their siRNA aptamers are unique to Johns Hopkins and the first to sensitize cancer cells to radiation. The current version is specifically targeted to prostate cancer, but he says with an adjustment to the chemical GPS, they can be adapted to target essentially any cancer.

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