Gene therapy for alcohol use disorder

Gene therapy could provide a one-off, sustained treatment for patients with severe alcohol use disorder, a study in monkeys suggests.

The study, published in Nature Medicine, showed that a gene therapy originally designed for Parkinson's disease significantly reduced alcohol consumption in macaque monkeys that had been conditioned to heavy drinking.

'Drinking went to almost zero,' said Professor Kathleen Grant from the Oregon National Primate Research Centre, who co-led the study. 'For months on end, these animals would choose to drink water and just avoid drinking alcohol altogether.'

Alcohol consumption induces the release of the 'happy hormone' dopamine, giving the buzz associated with drinking. However, sustained excessive drinking alters the dopamine release pathway, causing below-normal levels of dopamine. This cycle can lead to increased consumption of alcohol, increasing the risk of misuse.

Parkinson's disease is caused when the nerve cells in the part of the brain that produces dopamine die. The gene therapy is designed to deliver the gene for a protein called glial-derived neurotrophic factor (GDNF) to stimulate the growth of dopamine-producing cells.

To reset the dopamine reward pathway and boost dopamine production in the alcohol-conditioned macaques, the gene therapy was infused directly into an area of the brain known to be involved in addiction and reward.

'We targeted the cell bodies that produce dopamine with this gene to increase dopamine synthesis, thereby replenishing or restoring what chronic drinking has taken away,' said Professor Grant.

Prior to treatment, the macaques were consuming the human equivalent of about nine alcoholic drinks per day. After the gene therapy or control saline solution was administered, all macaques in the study went through cycles of enforced abstinence and voluntary water or alcohol consumption, to mirror common patterns of alcohol use in patients receiving treatment to help them stop drinking.

By the end of one year, all monkeys who had received the GDNF gene therapy had restored dopamine levels and reduced their alcohol consumption by more than 90 percent. In those monkeys who received a control infusion, alcohol consumption remained the same.

Alcohol is a contributing factor in more than 60 medical conditions, and alcohol misuse is the biggest risk factor for death and disability for 15- to 49-year-olds in the UK.

Given the non-reversible outcomes of gene therapy, potential side effects, and long-term efficacy will need to be investigated before using this approach in humans. Gene therapy that influences behaviour also raises ethical questions.

'It would be most appropriate for individuals for which all other forms of therapy have not worked,' Professor Grant said. 'You don't really want to go to an invasive and irreversible therapy unless someone's life is at stake.'