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Gene therapy delivered into the brain could treat alcohol misuse

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The reward pathway in the brain, which is initiated in response to a stimulus, such as alcohol. The stimulus (upper orange arrow) triggers the release of dopamine (blue arrows) by the ventral tegmental area (dark blue sphere). The dopamine travels to a number of different areas of the brain that then release dopamine (red arrows). These areas include the nucleus accumbens (red sphere), which initiates motor outputs (lower orange arrow) to sustain the pleasurable stimulus, the prefrontal cortex (pink), which shifts focus and planning towards the stimulus, and the amygdala, which is involved in emotions. The hypothalamus (orange sphere) is involved in coordinating the response by secreting hormones that control bodily functions

The reward pathway in the human brain, showing how a stimulus such as alcohol leads to the release of the chemical dopamine, which affects our emotional response and reinforces the release of further dopamine and other hormones

FERNANDO DA CUNHA/SCIENCE PHOTO LIBRARY

Alcohol misuse could one day be treated by a one-off gene therapy delivered into people’s brains, after a small trial in monkeys found this slashed their alcohol intake.

The gene therapy raised production of the signalling chemical dopamine, which is thought to be involved in addiction. If the treatment also works in people, it would probably be given only to those with the severest forms of alcohol misuse, because of the risks of the procedure to the brain.

Currently, the main treatment for alcohol misuse is talking therapies. While there are some medicines that can be used to reduce alcohol consumption, they don’t work for everyone.

Some people who want to stop drinking are thwarted by cravings for alcohol and stop taking these medicines. So, Kathleen Grant at Oregon Health & Science University in Portland and her colleagues wondered if gene therapy could be a treatment with long-lasting effects.

People who have drunk excessive amounts of alcohol for many years often have lower levels of dopamine in two regions roughly in the centre of the brain called the ventral tegmental areas. “This contributes to people needing alcohol for [feelings of] reward,” says Grant. Her team therefore designed a gene therapy that raised dopamine in these areas.

The group tested the approach in rhesus monkeys. As adolescents, these monkeys had chosen to drink relatively heavily when offered alcohol. By adulthood, they were choosing to consume the equivalent of several units of alcohol a day.

Grant’s team used a modified virus to deliver a gene encoding a signalling molecule called glial cell line-derived neurotrophic factor (GDNF) to the brain of four of these monkeys. GDNF is thought to promote the survival and functioning of dopamine-making brain cells.

The gene was delivered by drilling two small holes in the skull and injecting each ventral tegmental area with the infusion. Another four animals received an inert substance as a comparison.

Over the next 12 months, the treated animals chose to drink more than 90 per cent less alcohol than those in the comparison group. “They dropped their drinking down to near zero,” says Grant.

At the end of the year, the animals were euthanised and their brains examined. The researchers found that there were higher levels of both GDNF and dopamine in the targeted brain regions in the treated animals, compared with those in the other group.

However, it is still unclear exactly how the therapy works, says Grant. It could cause brain cells to produce more dopamine or dopamine could be removed more slowly. The GDNF also raised levels of other brain-signalling chemicals, including serotonin and noradrenaline (norepinephrine).

The technique used is impressive, but doctors may be wary of giving people this treatment unless they are severely ill with alcohol misuse, says Simon Waddington at University College London. “It’s a heck of a thing to have an injection into your brain of a gene therapy that you can’t switch off.”

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