Josh Mendell, associate professor of genetic medicine at the Johns Hopkins University School of Medicine, said that his lab has had a long-standing interest in miRNAs.
“We have been particularly interested in understanding how miRNAs are regulated in cancer cells and how aberrantly expressed miRNAs influence cancer cell behavior. We have found that specific miRNAs are often downregulated in cancer cells and restoration of expression of these miRNAs can potently inhibit tumorigenesis. This led us to test the idea that delivery of such antitumorigenic miRNAs could represent a novel therapeutic strategy for cancer.”
Dr. Mendell’s team focuses on liver cancer for many reasons. “The liver is one of the most accessible tissues for delivery of nucleic acid-based therapeutics. So it made sense to try this strategy first in a tissue where delivery would present less of a technical obstacle. Additionally, hepatocellular carcinoma is an aggressive cancer for which few, if any, effective therapies exist. So there is a great clinical need for new therapeutics for this disease.
“To deliver the microRNA in our study, we teamed up with Reed Clark and Jerry Mendell’s groups at Nationwide Children’s Hospital to develop adeno-associated virus (AAV) vectors that would express the miRNA. This is a nontoxic viral gene delivery platform, currently being used in clinical trials for other diseases that can efficiently carry gene products to the liver.”
Dr. Mendell’s team demonstrated that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. They showed that expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2.
“Systemic administration of this miRNA in a mouse model of HCC using AAV results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. We were excited by the potent therapeutic response as well as the apparent lack of toxicity of the miRNA treatment strategy. Since miR-26a is also lost in human HCC tumors, we think that with further study, this strategy may eventually see clinical use.”