21 June 2007

Gene therapy vs. Parkinson’s

The first attempt at gene therapy against Parkinson's disease has yielded promising results and is safe, according to early data from a ground-breaking experiment.

The first attempt at gene therapy against Parkinson's disease has yielded promising results and is safe, according to early data from a ground-breaking experiment.

The pilot study, conducted among 11 men and one woman in New York, marks the first-ever use of a "Trojan horse" technique against the tragic disease.

The technique entails taking a gene and tucking it inside a disabled cold virus, which is then injected into a key area of the brain. The harmless virus "infects" the local cells and thus stealthily delivers the corrective piece of genetic code.

Significant improvements
The 12 volunteers, all of whom have advanced Parkinson's, showed significant improvement in trembling, jerkiness and other symptoms, and none had any side effects, according to an assessment carried out a year after the operation.

The paper, appearing Saturday in the British journal The Lancet, could be an important spur for gene therapy.

In the 1990s, the dramatic rise of biotechnology spurred hopes of a "new dawn" for medicine in which inherited diseases could be wiped out by simply replacing the faulty genes in targeted cells with the right ones.

More complex than thought
But this vision became darkened by setbacks as scientists gradually realised that an individual's genome is a complex, interwoven tapestry -and substituting one gene with another can have far-reaching consequences elsewhere.

In 1999, this frontier research was blighted by the death of an 18-year-old American volunteer, Jesse Gelsinger, whose immune system ran amok following a gene transplant to fix a liver enzyme deficiency.

In 2002, French researchers were stunned when three out of 10 children they had cured with corrective genes to fix X-SCID, an inherited immunodeficiency disorder, suddenly developed leukaemia.

In this climate of deep prudence, researchers led by Matthew During, a professor at Cornell University's Weill Medical College, Cornell University, were placed under tight constraints in their experiment, which aimed primarily at testing for safety.

Parkinson's is an incurable, degenerative disease of the central nervous system that causes uncontrollable shaking, along with impaired speech and movement. In approximately one third of cases it also results in dementia. The disease affects at least one percent of people over the age of 65.

The cause is a loss of dopamine, a chemical messenger that helps direct movement. The substance is provided in a part of the brain called the substantia nigra.

Attempts to treat Parkinson's have focussed essentially on providing a pharmaceutical substitute for dopamine or on restoring or protecting dopamine-producing cells.

A different approach
During's team took a different tack, though. They aimed at part of the brain called the subthalamic nucleus, which becomes hyperactive as a result of Parkinson's and "blocks" signals to the nervous system, thus hampering motor control.

Using a magnetic resonance imaging (MRI) scanner to pinpoint their operations, the team delicately delivered a gene that controls an enzyme, glutamic acid decarboxylase (GAD), into the volunteers' subthalamic nucleus.

The idea was to use the gene as a switch to reverse the subthalamic nucleus' activity, turning it into an inhibitor rather than exciter of motor output signals.

None of the patients suffered any ill-effects from the surgery, or from the transplanted gene. Within three months of the operation, they reported substantial improvements in the side of the body that was opposite to the brain hemisphere where the gene was delivered, and the improvement continued until 12 months, the endpoint of the trial.

The researchers say the results, while preliminary, are encouraging, especially as US health watchdogs only gave them cautious authorisation for a gene transplant on one side of the brain, not both.

Caution advised
But Parkinson's researcher Jon Stoessl of the University of British Columbia, expressed caution.

The long-term effect of this therapy on the subthalamic nucleus' role in learning remains unclear, he said in a commentary, also carried by The Lancet.

Another unknown is whether the virus, even though disabled and transferred to only a tiny part of the brain, could affect neighbouring structures, he said.

Finally, there was no proof yet that this technique was any more effective than tried-and-tested implants to stimulate the subthalamic nucleus, Stoessl said. – (Sapa-AFP)

Read more:
Gene therapy – what you should know

June 2007


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