June 21, 2009

Engineered Viral Vectors Target Painful Nerve Diseases

Specially designed virus-derived vectors "“ engineered not to cause disease "“ can take therapeutic genes to the malfunctioning peripheral neurons outside the spinal cord and brain, alleviating the pain and other dysfunction that can result from a chronic disease or drug treatment, said researchers from Baylor College of Medicine and the University of Glasgow in a report in the current issue of the Journal of Clinical Investigation.

"These disorders that affect the dorsal root ganglion neurons can be extremely painful and difficult to treat," said Dr. Lawrence C.B. Chan, director of the BCM Diabetes and Endocrinology Research Center and a professor of medicine and molecular and cellular biology at the College. For example, shingles is extremely painful as is diabetic neuropathy, he said.  Drugs, particularly those used to fight cancer, can also cause a similar condition.

"The challenge is to deliver the beneficial genes specifically to the diseased nerve cells, or "Ëœneurons', and not to the neighboring unaffected cells or tissues," said Chan.

To correct this problem, Chan and his colleagues generated special "helper-dependent" adenoviruses that attach only to dorsal root ganglion neurons. Helper-dependent adenoviruses lack all the viral genes and are much less likely to cause disease. Chan and his colleagues used these adenoviruses to take therapeutic genes directly to the malfunctioning nerves of mice with Sandhoff disease, a disorder that causes degeneration of the central nervous system.

He and his colleagues found that their adenovirus took the missing Hexb gene to the malfunctioning nerves and corrected the problem with high efficiency.

"We are hopeful that this strategy, which we believe to be novel, could fill an immediate need in applying targeted gene therapy for DRG (dorsal root ganglion) disorders," the authors wrote.

The mice showed little evidence of inflammation or other problems that have plagued adenovirus vectors for gene therapy in the past.

"There are many potential clinical applications of the treatment strategy that we developed in this investigation," Chan and his colleagues wrote. "For example, diabetic neuropathy is the most common chronic complication of diabetes, affecting millions of people in the United States. Many of these individuals experience neuropathic pain caused by sensory neuron dysfunction."

An advantage of this approach is that it could be adapted to target difficult-to-reach neurons in different neurological diseases. Chan and his colleagues anticipate that this technique could be used in treatment of painful neuropathies in people in the near future.

Others who took part in the research include: Tomoya Terashima, Kazuhiro Oka and Hideto Kojima, all of BCM and Angelika B. Kritz and Andrew H. Baker, of the British Heart Foundation Cardiovascular Research Centre at the University of Glasgow in the United Kingdom.

Funding for this work came from The National Institutes of Health, the Medical Research Council in the United Kingdom, the Uehara Memorial Foundation in Japan and the Betty Rutherford Chair from St. Luke's Episcopal Hospital.


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