Monday, January 28, 2008

Gene Therapy for Chronic Pain

Researchers use gene therapy to stop pain signals before they reach the brain.

The pain gate: When we suffer pain--whether from a stubbed toe or a metastasized tumor--pain signals are transmitted to the brain from around the body through these groups of sensory neurons, called dorsal root ganglia (DRG). A new gene-therapy technique intercepts pain signals at the DRG using a gene for a naturally produced opiate-like chemical. On the right, the cells of a rat's DRG glow green with a marker for the opiate-like gene one month after it was injected into the rat's spinal fluid. On the left are DRG cells from a control rat injected with saline solution.
Credit: PNAS

A new kind of gene therapy could bring relief to patients suffering from chronic pain while bypassing many of the debilitating side effects associated with traditional painkillers.

Researchers at Mount Sinai School of Medicine injected a virus carrying the gene for an endogenous opioid--a chemical naturally produced by the body that has the same effect as opiate painkillers such as morphine--directly into the spinal fluid of rats. The injections were targeted to regions of the spinal cord called the dorsal root ganglia, which act as a "pain gate" by intercepting pain signals from the body on their way to the brain. "You can stop pain transmission at the spinal level so that pain impulses never reach the brain," says project leader Andreas Beutler, an assistant professor of hematology and medical oncology at Mount Sinai.

The injection technique is equivalent to a spinal tap, a routine procedure that can be performed quickly at a patient's bedside without general anesthesia.

Because it targets the spinal cord directly, this technique limits the opiate-like substance, and hence any side effects, to a contained area. Normally, when opiate drugs are administered orally or by injection, their effects are spread throughout the body and brain, where they cause unwanted side effects such as constipation, nausea, sedation, and decreased mental acuity.

Side effects are a major hurdle in treating chronic pain, which costs the United States around $100 billion annually in treatment and lost wages. While opiate drugs can be very effective, the doses required to successfully control pain are often too high for the patient to tolerate.

"The side effects can be as bad as the pain," says Doris Cope, director of the University of Pittsburgh Medical Center's Pain Medicine Program. Achieving the benefits of opiate treatment without their accompanying side effects, Cope says, would be a "huge step forward."

Beutler hopes to do just that. "Our strategy was to harness the strength of opioids but target it to the pain gate, and thereby create pain relief without the side effects that you always get when you have systemic distribution of opioids," he says.

Several groups have previously attempted to administer gene therapy for pain through spinal injections, but they failed to achieve powerful, long-lasting pain relief. The new technique produced results that lasted as long as three months from a single injection, and unpublished follow-up studies suggest that the effect could persist for a year or more.

Beutler credits his team's success to the development of an improved virus for delivering the gene. The team uses a specially adapted version of adeno-associated virus, or AAV--a tiny virus whose genome is an unpaired strand of DNA. All the virus's own genes are removed, and the human endogenous opioid gene is inserted in their place. Beutler's team also mixed and matched components from various naturally occurring AAV strains and modified the genome into a double-stranded form. These tweaks likely allow the virus to infect nerve cells more easily and stick around longer.

Once the virus is injected into the spinal fluid and makes its way into the nerve cells of the pain gate, it uses the host cells' machinery to churn out the opioid protein--which then goes to work blocking pain signals on their way to the brain. Normally, the gene is rarely activated. But the version used for therapy has no such limitations because the gene carried by the AAV has been modified to continuously produce the opioid chemical.

Cope says that using endogenous opioids is inherently superior to injecting synthetic opiate drugs directly into the spinal fluid, an approach that requires the installation of a pump in order to deliver the drugs over a long time period. "It's kind of a holy grail," she says. "If the body's own system for pain control were activated by genetic expression, that would be superior to an artificial medication."

In Beutler's study, which was published this week in PNAS, rats were surgically modified to have a stronger than usual response to pressure on their paws, mimicking the effects of so-called neuropathic pain. The gene-therapy treatment effectively restored the rats to a normal level of pain sensitivity. The team also tested a nonopioid gene, which produced comparable pain relief through an entirely different mechanism. But while the opioid gene's effects will likely extend to humans, who respond to opiates the same way rats do, the nonopioid's effects may be rat specific.

The Stockholm-based company Diamyd Medical has been developing a different approach to gene therapy for chronic pain that also bypasses the side effects of standard pain treatment. The approach uses a deactivated version of herpes simplex virus (HSV). HSV can be administered straight through the skin as it naturally finds and infects peripheral nerves and travels to the spinal cord on its own. Darren Wolfe of Diamyd says that this method is superior to spinal injection because it's safer and easier, and it can be administered repeatedly.

Because of these considerations, the HSV method may be preferable for treating localized pain. However, when chronic pain involves multiple areas of the body--as it often does with, for example, metastasized cancers--going straight to the pain gate could work more efficiently.

While both of these methods have proved effective in animal models of pain, their efficacy in human patients remains to be shown. Diamyd recently applied to the FDA to begin phase I clinical trials, and Beutler estimates that his approach could be tested on humans in as few as three years.

TV for the Visually Impaired

Using a new algorithm, researchers are trying to enhance picture quality so that those with macular degeneration can enjoy television.

Enhanced vision: Researchers at the Schepens Eye Research Institute have developed software that lets users enhance the contrast of images on a television screen. In the image above, the screen is split: on the left is an unenhanced television picture, and on the right is a picture with the contrast enhanced.
Credit: Schepens Eye Research Institute
Watch enhanced video.
Compare normal and enhanced images.

Enjoying a favorite TV show can be difficult for someone with macular degeneration. Like many kinds of visual impairment, macular degeneration makes the images on the screen seem blurred and distorted. The finer details are often lost. Now researchers at the Schepens Eye Research Institute have developed software that lets users manipulate the contrast to create specially enhanced images for those with macular degeneration.

"Our approach was to implement an image-processing algorithm to the receiving television's decoder," says Eli Peli, a professor of ophthalmology at Harvard Medical School and the project leader. "The algorithm makes it possible to increase the contrast of specific size details."

The researchers focused their work on patients with age-related macular degeneration, a disease in which the macula--the part of the eye that's responsible for sharp, central vision--is damaged. According to the American Macular Degeneration Foundation, more than 10 million Americans suffer from the disease, which often leaves those afflicted with a central blind spot. A patient's remaining vision is often blurred, making it extremely difficult for people to watch television or even read the paper, says Mark O'Donoghue, clinic director of the New England College of Optometry's Commonwealth Avenue Clinic. "This is really new and fascinating to read about," says O'Donoghue. "I recognize the basic facts in the technology and the path of physiology in which [Peli] is doing this, and it is innovative."

Peli and his group currently have the new software running on a computer in their lab, but they're expecting to receive a prototype system built by Analog Devices in April 2008.

Peli's group discovered that patients suffering from macular degeneration could not perceive high-frequency waves in the visible spectrum, which left them unable to see fine details.

In order to give the patient a much better chance of discerning the image, the researchers designed an algorithm that specifically increases the contrast over the range of spatial frequencies that the visually impaired could see: the middle and low frequency waves. Ultimately, Peli says, the system enhances the contrast of the picture, and the result is that the finer details are more evident.

The contrast can be adjusted by a user in much the same way that one would change the volume on a TV using a remote control. O'Donoghue likens the system to a stereo equalizer for the eyes that allows TV watchers to fine-tune the picture.

To measure the amount of image enhancement that individuals prefer, the researchers recently conducted a study using 24 patients with visual impairments and 6 normal-sighted people. The subjects sat in front of a television and watched four-minute videos, adjusting the level of contrast with a remote control. The researchers found that all the subjects--even the normal-sighted people--wanted some level of enhancement, and the majority of the time a subject chose the same level of enhancement whether they were watching a dark scene or fast action, says Peli. (The amount of enhancement selected correlated to the severity of the subject's vision loss.) The study was published last month in the Journal of the Optical Society of America.

One day, this system could transform watching TV alone or with the family into a more "rewarding experience" by making it easier for people to pick out the objects of interest from their surroundings, says Tom O'Donnell, an assistant professor at the University of Tennessee's Hamilton Eye Institute.

Peli hopes that the system will eventually be incorporated into the menu options for all televisions. Ideally, people will have the option to see an enhanced view just as the hearing impaired have the option to call up captions, he says.

Pioneer PDP-5080XD Review

50in Plasma
The best HD or SD picture bar none, at a price.
HD Ready: yes
Resolution: 1,365 x 768
Rating: 95%


Alongside the Pioneer PDP-5080XD sits its identical (almost) sibling, the PDP-508XD. You will find both units retailing for around the same amount with the 5080XD having the advantage of a pedestal stand included in the package, and the 508XD endowed with some extra features.

These features include a USB port, picture-in-picture (Pip) functionality, sub-woofer output, ISF C3 (Custom Calibration Configuration) compatibility and Intelligent Brightness Control.


You pay a little bit more for a Pioneer, but some of this premium has obviously been directed towards quality materials with the screen just oozing quality from every pour. The glossy black slim-framed PDP-5080XD will bring envious glances from friends and neighbours alike.


With an all new 8th generation screen (dubbed 'Kuro'), the Pioneer PDP-5080XD promises Black Levels to match and better anything seen to date from other Plasma and LCD TV manufacturers.

Screen: 50in 16:9
Sound System: Nicam
Resolution: 1,365 x 768
Contrast Ratio: 16,000:1
Other Features: PURE Drive 2HD, Digital Noise Reduction (DNR), Direct Colour Filter III, MPEG NR (Noise Reduction). .
Sockets: 3 HDMI, 3 SCART, Component Video, Composite Video, S-Video, PC input.

Even with a whole host of new technological innovations, this new generation of screens will not be found wanting connectivity wise. The PDP-5080XD features 3 HDMI inputs, 3 scarts, Component Video, Composite Video and S-Video. Additionally, there is a CI slot and USB port.

Picture processing technology on the PDP-5080XD comes in the shape of Pioneer's PURE DRIVE 2HD which has been designed to eliminate video noise by minimising intermediate analogue-to-digital and digital-to-analogue conversions. Image processing has been optimised for Plasma screens, and to work with Pioneer's latest 8th generation screen.

PURE DRIVE 2HD is complemented by i-CLEAR Drive which employs multi bit digital video processors to increase the range of gradation levels, producing more subtle colour differences.

The PDP-508XD retains all of the technological wizardry of its predecessors. Pioneer has once again deployed its 'Deep Waffle Rib' structure designed to reduce cross-pixel light and colour contamination.

Speakers are optional on the PDP-5080XD, Pioneer assuming that the screen will more often than not form the centre piece of a home cinema system.


The Black Level performance of the PDP-5080XD is a revelation, with a purity that stands head and shoulders above offerings from any other Plasma or LCD manufacturer out there. The subtlety of graduation across dark scenes is nothing short of spectacular.

High Definition (HD) viewing from Blu-ray or HD DVD is stunning, with a sharpness and level of detail that is at least as good as the best from other manufacturers.

Colours on the PDP-5080XD are exceptionally vibrant and display an almost complete absence of some of the faults and niggles displayed by lesser Plasma screens. Colour saturation is class leading, and the realism of skin tones for example, illustrates just how accomplished this screen is.

Standard Definition (SD) pictures are not the best we have seen but they are close, which is saying something for a 50in screen. SD pictures are easily the best we have seen on a large (50in +) Plasma or LCD even with low quality Freeview sources.

Now we come to the negative, although for a number of enthusiasts out there it won't be seen as such. To get the most out of the PDP-508XD takes a great deal of tweaking of the various picture processing settings. Without this tweaking, the PDP-5080XD has some noticeable shortcomings. In fact, 'out of the box' the PDP-5080XD is quite ordinary in some respects - in particular, fast action scenes suffer from a certain amount of juddering.

By tweaking the PDP5080XD's Drive Mode settings we were able to eradicate the motion problems, and the important point is that all aspects of the PDP-508XD can be improved. However, unlike Panasonic Plasma's for example, the PDP-5080XD has a 'specialist' feel about it, and this won't suit some.

This should take nothing away from the PDP-5080XD, which is in our opinion the best performing flat panel out there - it just requires a little tender loving care (we will be producing a more comprehensive 'tweaking' guide for the PDP-508XD soon).


If you want to pull this Pioneer straight out of the box and have little or no interest in 'tinkering' with its performance then the PDP-5080XD will make an ideal high end choice.

The extra features offered by the PDP-508XD will appeal to the TV enthusiasts out there, not necessarily those of you who enjoyed poking a screwdriver into the back of your old CRT, but those of you interested in the technicalities of getting the very best picture from your plasma.

The Pioneer PDP-5080XD has given us all at HDTVorg the feeling that the days of CRT outperforming plasma with SD sources are numbered. The PDP-5080XD is not quite there yet, but the difference is negligible, and with HD sources the PDP-5080XD in our opinion brings you the ultimate home viewing experience.