NIH awarded researchers at Allegheny General Hospital (AGH) a $1.7 million grant over four years to progress development of a nonviral gene therapy approach that uses ultrasound to deliver DNA directly to target cells. The funds will support the use of ultrasound-assisted gene transfer in animals as a treatment for xerostomia, a complication of radiation therapy for head and neck cancer resulting from irreparable damage to salivary glands, which causes dry mouth and speech, chewing, and swallowing problems.

The AGH team hopes their studies confirm that the approach can bypass problems associated with viral vector-based methods of gene delivery, which tend to be short-lived due to the body’s immune response. “What we are trying to do is avoid the use of viruses altogether by focusing instead on a more mechanical approach to facilitating the gene transfer,” comments lead researchers Michael Passineau, Ph.D., director of the gene therapy program at AGH’s Allegheny Singer Research Institute (ASRI).

The delivery approach uses ultrasonic frequency sound waves to temporarily modify the permeability of cell membranes and allow DNA to enter cells directly. The process involves infusing a solution of gene construct and microbubbles directly into the treatment site, then applying a low-frequency ultrasound beam to the same area. This causes the bubbles to vibrate and eventually implode, generating a shockwave that briefly makes the cell membrane permeable to the gene construct.

The xerostomia therapy involves delivering the aquaporin-1 (AQP1) fluid transporter gene directly into the cells of the salivary gland. “The idea is that if you can express aquaporine-1 in the still-viable ductal cells of the salivary gland, you can pull water from the blood into the ductal network, fill up the gland and have it drain into the mouth,” Dr. Passineau explains.

An initial human study at NIH’s Clinical Center demonstrated that the benefits of viral vector-delivered AQP1 as a treatment for xerostomia were short-lived due to host immune responses. The animal studies planned by AGH hope to demonstrate that ultrasound-mediated delivery of the gene has a much longer-lasting beneficial effect. “We have already shown in the laboratory that the technique itself works,” Dr. Passineau adds. “With the NIH’s support we are very excited to now focus our efforts on proving its therapeutic capability.”

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