Gene therapy to brain may treat major depression.
The Science Translational Medicine study demonstrated that a brain protein known as p11 in a single, small brain area, the nucleus accumbens, is critical to the feelings of reward and pleasure that are often missing in depression.
While investigators believe that depression is a complex disorder that likely involves a number of brain areas and neural circuits, they say their findings suggest that restoring p11 may significantly alter the course of depression in humans.
"Applying molecular neurobiology and gene therapy to depression could dramatically alter the approach to psychiatric diseases," said Dr. Michael Kaplitt, associate professor and vice chairman for research of neurological surgery at Weill Cornell Medical College and a neurosurgeon at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
In 2006, Dr. Greengard and his Rockefeller colleagues discovered that the p11 gene appears to play a key role in depression. They found p11 protein is needed to bring receptors that bind to the neurotransmitter serotonin to the surface of nerve cells. In the brain, serotonin regulates mood, appetite and sleep, among other functions, and most antidepressants seek to regulate serotonin.
"In the absence of p11, a neuron can produce all the serotonin receptors it needs, but they will not be transported to the cell surface and therefore won't stick out and latch on to the neurotransmitter," said Kaplitt.
So the researchers decided to disable function of the p11 gene in mice using a virus, which would produce an siRNA-small pieces of double-stranded RNA-that blocked the gene's expression. Once they showed this could be done, they chose to selectively target p11 expression in the nucleus accumbens brain area because human functional MRI studies at Weill Cornell had shown this area to be particularly affected in depressed patients.
The mice without p11 all exhibited depression-like behaviors. That prompted Dr. Kaplitt and his team to adapt the gene therapy vehicle they had successfully tested in Parkinson's disease patients in a phase I clinical trial reported in the Lancet in 2007. The therapy uses an inert "smart" virus as a Trojan horse to enter brain cells and deposit a genetic payload into the genome of neurons. These new genes then produce their protein.
To treat Parkinson's disease Dr. Kaplitt used the virus to deliver glutamic acid decarboxylase (GAD), the enzyme that synthesizes the neurotransmitter GABA. In the current study, he inserted the p11 gene into the virus and delivered them to the nucleus accumbens of the p11-free mice. The treatment effectively reversed depression-like behaviors in the mice.
The report has been published in Science Translational Medicine. (ANI)
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|Publication:||Asian News International|
|Date:||Oct 21, 2010|
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