Gene Therapy Unlocks Some Mysteries of Depression

The field of gene therapy can count another success, albeit a rather small one. Researchers at Weill Cornell Medical College were able to treat depressive behavior in a mouse model of depression using gene therapy techniques. The research also marks an advance in our understanding of the neurobiology of depression.

Dr. Kaplitt and colleagues created a mouse that expresses lower levels of a specific protein known as p11. The p11 protein promotes the activity serotonergic neurons in the brain, a longstanding target of depression treatment drugs such as SSRIs (selective serotonin reuptake inhibitors. This knockdown mouse displayed signs of depression when subjected to specific behavioral tests.

The way that they created the knockdown mouse was the interesting part. Researchers used an adeno-associated virus to “infect” or introduce a small-interfering RNA (siRNA) into a specific region of the brain called the nucleus accumbens. As a result, cells within this discrete brain region produced less of the p11 protein.

By using gene therapy to introduce this particular siRNA, the scientists were able to influence the behavior of the animal. Treated mice performed poorly on the forced swim test and the tail suspension test, which is consistent with depressive symptomatology. Curiously, when these siRNA treated mice were given antidepressant medications, their performance did not improve. Previous research showed that “depressed” mice (those that were stressed or postpartum) performing poorly of behavior tests would perform better if treated with an antidepressant. These results suggest that variations in human p11 may explain why some people do not experience a benefit from antidepressants.

The implications for human treatment are rather profound. The p11 protein appears to represent a newmolecular target for the development of depression treatments. Current treatment is focused on interfering with serotonin and norepinephrine reuptake. With a new target, pharmaceuticals or gene therapies could be developed to augment p11 expression.

Indeed, that is the immediate direction of future work. Studies are underway in non-human primates to use the adeno-associated virus to upregulate the levels of p11. The idea being that too little p11 not only underlies depression but also makes patients refractory to treatment. As with other avenues of gene therapy research, though, the road is long. A significant amount of efficacy and safety studies need to be performed before we see a gene therapy treatment of this nature in the clinic.