NIH Awards Allegheny General Hospital Researchers $1.7 Million Grant to Study Pioneering Approach To Gene Therapy

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The National Institutes of Health (NIH) this week awarded researchers at Allegheny General Hospital in Pittsburgh a $1.7 million grant to support the study of a pioneering approach to gene therapy that may offer new hope for the treatment of chronic illnesses. The study will initially look at its potential to treat a condition called xerostomia.

“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,” said Dr. Michael Passineau.

For all of the potential that gene therapy has demonstrated in clinical trials over the past two decades, delivering sustained, long-term disease management has been a challenge largely unmet by conventional gene therapy techniques. This week, the National Institutes of Health (NIH) awarded researchers at Allegheny General Hospital (AGH) a $1.7 million grant to support the study of a pioneering approach to gene therapy that may offer new hope for chronic illness through its use of an innovative ultrasound procedure, instead of a virus, to facilitate the transfer of therapeutic DNA into cells.

Called ultrasound-assisted gene transfer, the technique will be explored by the AGH team in an animal model study to determine its efficacy in the treatment of xerostomia, a high-incidence complication of radiation therapy for head and neck cancer in which the salivary glands are irreparably damaged. The loss of gland function causes dry mouth and the impairment of normal oral functions such as speech, chewing and swallowing.

The NIH award is one of the largest grants ever received by AGH and will be distributed over the course of four years. The project is being led by Michael Passineau, PhD, Director of the Gene Therapy Program at Allegheny Singer Research Institute (ASRI), the research arm of AGH and its parent, the West Penn Allegheny Health System. Co-investigators in the study include AGH radiation oncologist Mark Trombetta, MD, and AGH cardiologist Robert Biederman, MD.

“Dr. Passineau and his team are on the leading edge of a promising new direction in gene therapy that may one day allow for the more effective treatment of chronic diseases, a capability that currently eludes us with existing viral gene transfer techniques. This NIH grant is another scientific milestone for AGH and ASRI and a resounding endorsement of not only Dr. Passineau’s ingenuity and outstanding capabilities, but the impressive scope and quality of medical research being conducted within our organization,” said Joseph Ahearn, MD, ASRI’s Chief Scientific Officer and Vice President.

Gene therapy involves the use of DNA as a pharmaceutical agent to treat disease – introducing new genes to a patient’s cells to replace missing or malfunctioning genes. The most common form of the treatment involves using DNA that contains a functional, therapeutic gene in order to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that houses a therapeutic protein drug (rather than a natural human gene) to provide treatment.

For gene therapy to work, therapeutic DNA must be packaged within a "vector" that is able to penetrate cells within the body. Viruses are the most commonly used vectors to achieve this task. Once inside the cell, DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease.

“Getting DNA drugs into cells and sustaining the therapeutic benefit they may offer to a patient is the paramount challenge of gene therapy. While viruses have proven to be exceptionally good DNA delivery vehicles, viral gene therapy is ultimately self-limiting due to the body’s inevitable immune system response. The treatment may work, but likely only for a short time and the viral vector can only be used once,” said Dr. Passineau, who is also an Assistant Professor of Medicine in AGH’s Division of Cardiovascular Medicine and a lead scientist within the AGH Cardiovascular Institute Center for Cardiovascular Research and Innovation.

“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.”

Ultrasound-assisted gene transfer is based on a process called sonoporation – or the use of sound (typically ultrasonic frequencies) to modify the permeability of cell membranes and allow DNA to pass through. After mixing a gene drug with a solution of microbubbles and infusing it into the treatment site, a very powerful, low frequency ultrasound beam is directed into the area. Like an opera singer shattering a crystal glass, the ultrasonic beam causes the bubbles to vibrate in the acoustic field and eventually implode. The implosion creates a shock wave that briefly opens the cell membrane and allows the gene drug to enter.

In his study, Dr. Passineau will use sonoporation in an attempt to restore the function of damaged or destroyed salivary glands by infusing a genetic drug called aquaporin-1 (AQP1) into the cells of the gland. Expressed mostly in the kidney where it helps in the dilution of urine, AQP1 encodes a protein that transports fluid by forming pores, or water channels, in cell membranes.

Using a syringe, the gene/microbubble solution is delivered directly into the salivary gland through its opening in the mouth. The ultrasound beam is then administered for just a few minutes. There is no need for surgery or anesthesia.

“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 said.    

Several pre-clinical studies have already demonstrated the potential of AQP1 gene therapy to provide substantial relief from xerostomia. Additionally, the first clinical gene therapy study to treat damaged salivary glands, using a viral vector to deliver the AQP1 gene, began enrolling patients at the NIH’s Clinical Center in 2009.

“The downside so far [in the previous studies] is that like most viral gene therapy applications, the success of the treatment has been short lived because of the host’s immune response. Our hope is that ultrasound assisted gene transfer will extend the benefits indefinitely,” Dr. Passineau said. “We have already shown in the laboratory that the technique itself works, and with the NIH’s support we are very excited to now focus our efforts on proving its therapeutic capability.”

According to Dr. Trombetta, advances in radiation therapy such as IMRT (intensity modulated radiation therapy), IGRT (image guided radiation therapy), and salivary gland stimulants and protectors have helped reduce the incidence and severity of xerostomia among the more than 40,000 patients who are treated each year for head and neck cancer in the United States. Nevertheless, the condition remains a significant complication even at the most experienced cancer centers like AGH.

“Xerostomia is an extremely difficult side effect of head and neck radiation therapy that can severely compromise a patient’s quality of life. We are thrilled to be participating in such groundbreaking research that may one day help us further relieve the burden of this condition,” Dr. Trombetta said.

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