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Ultrasound Offers Breakthrough In Gene Therapy

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Canavan disease – a degenerative disease that causes difficulty learning and mental retardation due to progressive brain cell damage.

– a disorder in which the blood does not clot properly, so that sufferers continuously bleed (possibly to death) from wounds or bruises.

Celiac disease
– an autoimmune disorder in which the body reacts to a gluten protein found in wheat, painfully inflaming the small intestine and interfering with nutrient absorption.
These three disorders have something in common; they are all caused by errors in the genetic code. People diagnosed with Down syndrome, Huntington’s disease, cystic fibrosis, sickle cell anemia, Duchenne muscular dystrophy and many other genetic disorders are in the same boat.

Theoretically, gene therapies could be used to replace misplaced and miscopied and missing DNA with healthy code, potentially curing patients born with genetic defects. Up to this time, however, most efforts have either failed to succeed in the long term or have seriously harmed test subjects.

Without a cure, patients have focused on managing their disorders; people with celiac disease protect themselves by removing all gluten from their diets; those with hemophilia can receive artificial clotting factors and take care not to injure themselves. Still, even with careful management, many of these disorders result in disability and/or early death.

Researchers from Allegheny Singer Research Institute (ASRI) at Allegheny General Hospital (AGH) hope a new method of delivering healthy genes directly to target cells would give hope to people who suffer from painful and debilitating genetic disorders. The National Institutes of Health recently offered the hospital a $1.7 million four-year grant to develop a gene therapy technique that uses ultrasound to help healthy DNA get to where it needs to go.

Viral Vectors:
A virus has been used as the vector – the carrier – of the DNA in research up to this point, because viruses conveniently shoot their DNA into the cells of their host. Researchers have tried treating patients by loading a virus with a specific gene and injecting the virus into the pertinent cell area to deliver the DNA into the individual cells. The technique has failed, for the most part, because the body’s immune system attacks the virus as an invader.

In December of 2011, a team of British and American researchers did have early success in treating hemophilia B by delivering a factor 9 gene into patients’ cells through an adeno-associated virus-8 vector, one attracted to the liver. The patients were able to produce between two and 12 percent the normal amount of factor 9 themselves (as opposed to less than one percent), enabling some of the patients to stop infusing clotting factor treatments. Some patients experienced an immune response seven to nine weeks after the virus injection, which required steroids to bring under control.

Most viral vector treatment successes during the past fifteen years have been short lived, and patients have generally had to deal with the side effects of anti-rejection drugs.

This new technique would completely skip the virus intermediate and would use ultrasound to allow the modified DNA to enter cells. Researchers are mixing a gene construct with microbubbles and introducing the solution to a treatment site. An ultrasound beam applied to the site would then vibrate the bubbles, making them implode, resulting in a shockwave that temporarily makes cell walls less solid, allowing the new DNA to slip into the individual cells.
"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 lead researcher Michael Passineau, Ph.D., director of the gene therapy program at ASRI.

The treatment will first be addressing xerostomia – dry mouth – in which people do not produce enough saliva and therefore have trouble talking, chewing, and swallowing. It is often a complication of salivary gland damage from certain medications or from radiation treatments for mouth and throat cancers. The researchers will inject healthy gene constructs of the aquaporin-1 fluid transporter gene into the saliva gland tissues of pigs, and will move on to human testing if there is success.

"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. Passineau believes that if the treatment works, it could be used to address genetic problems that affect the heart, pancreas and kidneys.
This research pops opens a massive box of possibilities for helping people who suffer painful deterioration because their bodies fail to produce one protein or another, giving them a chance at greater physical well-being. At the same time, this therapy involves meddling with genes… and we do not completely understand what all certain DNA coding can affect. Such research requires great respect and care, that in our effort to repair, we do not cause results we never intended.

Related Links:

NIH Funds Gene Therapy Using Ultrasound – Genetic Engineering and Biotechnology News
Grant To Fund Gene Therapy Study At Allegheny General Hospital – Trib Live News
European Agency Backs Approval of a Gene Therapy – The New York Times
Haemophilia Gene Therapy Shows Early Success – BBC News (Dec 2011)
Woman’s Death Calls Gene Therapy Into Question – AP (Sept 2007)

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