Antidepressant target discovery could lead to gene therapy

Courtesy of Northwestern Medicine

In 2010, researchers at Weill Cornell Medical College thought they hit on a novel way to treat depression--by delivering a gene called p11 directly to the brain. The gene therapy looked promising in mice but hasn’t yet moved into clinical trials.

Now, researchers at Northwestern University are revisiting the idea of gene therapy to treat depression. Investigators there have found that decreasing a set of proteins in the brain called HCN channels reduced depression-like behavior in mice. If the findings can be replicated in humans, they could aid scientists in developing novel gene therapies for millions of patients who do not respond to existing treatments for depression.

HCN channels are known to be involved in controlling the electrical activity of cells in the heart and brain. Recently, Northwestern researchers and others found that these channels might also play a role in the hippocampus, where they observed changes that suggest a link to behaviors that resemble depression.

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Armed with that theory, Dr. Dane Chetkovich, a professor of neurology and of physiology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurologist, sought to test a gene therapy in mouse models. So Chetkovich and his team surgically injected mice with a harmless virus engineered to express a gene that turns off HCN channel function in the neurons of the hippocampus.

"When the HCN channels stopped working, the mice behaved as if they'd been given antidepressant medications," Chetkovich said in a statement.

When the function of HCN channels was increased the opposite happened, giving the mouse depression-like symptoms. Chetkovich and his team measured this by timing how long mice would look for a way to escape an environment before giving up, a common benchmark test for depression used in preclinical studies. The results were published in the journal Molecular Psychiatry.

Gene therapy is an intriguing alternative approach to treating depression. Most current antidepressants work by increasing levels of neurotransmitters like monoamines, namely serotonin, dopamine and norepinephrine. But often these drugs take weeks or months for their effects to kick in. For some patients, existing antidepressants provide little or no relief, or they may stop working altogether.

This variation in efficacy is because depression is a heterogeneous disorder, and many additional biological mechanisms are likely at the root of depression but haven’t been uncovered yet. With more than one in 10 Americans ages 12 and older reportedly taking an antidepressant medication, the market for new antidepressants is large.

Researchers elsewhere are investigating HCN channels’ role in working memory, which can dramatically affect cognitive function and is a symptom of many neurological disorders, including schizophrenia.

"This work not only identifies a totally new treatment target for depression, it provides a detailed molecular description of the structures that need to be manipulated for it to act as an antidepressant and develops viral tools to do so," said Chetkovich, who is working with his lab to translate the gene therapy to human patients.

-here is the study
-read the Northwestern news

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