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Gene Therapy in Human Salivary Gland Shows Promise

Treatment could help cancer survivors with chronic dry mouth (Nov. 5)

Gene therapy can be performed safely in the human salivary gland, according to scientists at the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health (NIH).

This finding comes from the first safety study of gene therapy in human salivary glands. The results, published this week in the Proceedings of the National Academy of Sciences, also show that the transferred gene, Aquaporin-1, has the potential to help head-and-neck cancer survivors with chronic dry mouth. Aquaporin-1 encodes a protein that naturally forms pore-like water channels in cell membranes to help move fluid, such as occurs when salivary-gland cells secrete saliva into the mouth.

These initial results clear the way for additional gene-therapy studies in salivary glands, which present an ideal target for gene therapy. The glands are easily accessible, and once a gene is introduced, it has no obvious escape route into the bloodstream, where it could have unintended consequences.

In the early 1990s, Bruce Baum, DMD, PhD, and colleagues assembled a strong scientific case in animal studies that the transferred Aquaporin-1 gene, once expressed, will create new water channels in the impermeable salivary-gland cells and will allow water to flow through them. After rigorous reviews by the NIH and the FDA, the phase I protocol was launched and the first patients were treated in 2008.

The researchers gave 11 head-and-neck cancer survivors a single-dose injection of the Aquaporin-1 gene directly into one of their two parotid salivary glands, the largest of the major salivary glands. The gene was packaged in a disabled, nonreplicating adenovirus — the cause of the common cold when intact but incapable of causing a cold in this case. As is standard in gene-therapy studies, the virus served as the vector, or “Trojan horse,” to deliver the gene into the cells lining the salivary gland.

The scientists found that five participants had increased levels of saliva secretion, as well as a renewed sense of moisture and lubrication in their mouths, within 6 weeks. Of the six who didn't benefit from gene therapy, none had serious side effects. The most common side effect was a transient immune response against the disabled adenovirus.

“It is time to evaluate a different vector to deliver the Aquaporin-1 gene, one that will cause only a minimal immune response,” Baum said. “But these data will serve as stepping stones for other scientists to improve on this first attempt in the years ahead. The future for applications of gene therapy in the salivary gland is bright.”

Source: NIH; November 5, 2012.

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