Can Gene Therapy Cure Depression?

Season Fung

Depression is a very common disorder - according to the Office of National Statistics, it affected 1 in every 6 adults last summer. Although there are many factors that cause depression, Stanford Medicine approximates that 50% of the cause is genetic. However, there is no single defective gene that causes depression, unlike in Huntington's disease or cystic fibrosis.

How, then, is depression treated, you might ask? Well, the most common type of antidepressants, SSRIs (Selective Serotonin Reuptake Inhibitors), work to increase the amount of serotonin in your body, as serotonin is dubbed the ‘happiness hormone’. SSRIs work by blocking the reabsorption of serotonin (5-HT), so that the amount of serotonin in the synaptic cleft increases.

Although scientists have found many biomarkers that could potentially be used to detect depression, one particularly interesting theory is that the p11 gene can regulate depression. At first, this stemmed from researchers noting that many depressed mice lack the p11 gene. This p11 gene is important because the p11 protein is necessary to bring serotonin to the surface of nerve cells. More specifically, it activitates 2 serotonin receptors, 5-HT 1BR and 5-HT 4R. In 2013, scientists further found that a few serotonin (5-HT) receptors all interacted with a protein called p11, which meant that increased amounts of p11 could enhance the effects of the serotonin receptors.

To test the theory that increased p11 can boost serotonin levels, researchers used RNA interference to block the expression of p11 in mice brains. Then they used two routine tests for depression in mice, and the blocking of genes had the expected effect - the mice struggled less when held by their tails, and also swam more slowly when put in a container of water. Then, the researchers injected a vector containing the p11 gene into the same mice, which miraculously did reverse their depression-like symptoms!

That experiment has led to more research being done to see whether this could be replicated in humans. A comparison was done of 17 brains of dead people, some with depression, some without. It showed that in the nucleus accumbens (one key brain region that regulates depression), people with depression had much lower levels of p11 than the people without depression. This conclusion gave hope to the fact that if gene therapy could reverse these low levels of p11, the symptoms of depression could also be reduced.

Of course, there are many challenges to face before this proposed gene therapy could be used on humans. First of all, the model of depression in mice is very different to depression in humans, because the ‘tests’ for depression in mice only showed one aspect of depression, and do not display others such as anxiety. Also, the long term effects of boosting p11 levels could be unwanted, especially if a person’s depression has been decreased. No one knows what the consequences of an excessive expression of p11 looks like.

However, there still is some hope. The same researchers who reversed depression in mice, have used a gene therapy to treat Parkinson’s Disease. That gene therapy inserts an inert virus into brain cells, in order for them to start producing a specific gene, which in that case was the GAD gene. Patients with Parkinson’s who received this gene therapy had their motor symptoms greatly reduced, which is very promising. If a similar method of gene therapy was used to insert the p11 gene, perhaps gene therapy really could cure depression.

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