Researchers at the North Western Medicine University have shown that by manipulating a novel target in the brain using gene therapy, new treatments for depression can be found. Clinical depression is becoming a common phenomenon. It can cause severe symptoms and can affect how one feels, thinks, and handles daily activities, such as sleeping, eating, or working. If left untreated, it can also have life threatening results.
The researchers working on the study in context found that when a set of proteins called HCN channels were decreased, it reduced depression like behavior in mice. If the same could be replicated in humans, the findings could result in new therapies which could help millions of patients who do not respond to the existing therapies and treatment for depression.
The findings of the study were published recently in an issue of the journal ‘Molecular Psychiatry’.
Dr. Dane Chetkovich, study’s senior author and professor of neurology and of physiology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurologist remarked that drugs that are presently available for treating depression help most patients, but they stop working for some patients and don’t work from the get-go for others. Hence, there is a huge need for novel therapies to help patients desperate for alternatives to the available therapeutic options. The antidepressants available today work on the emotions and mood of a patient by enhancing the levels of neurotransmitters called monoamines, namely serotonin, dopamine and norepinephrine. But, since these drugs are not effective for many patients indicate that there are additional mechanisms underlying depression that need to be discovered. Newer therapies could be used to help such patients.
In an earlier research at Chetkovich’s lab, it was found that those mechanisms might involve the hippocampus. It is the region of the brain important for learning, memory and emotional regulation. The researchers discovered that changes to HCN channels, typically involved in controlling the electrical activity of cells in the heart and brain, had a critical role to play in behaviors linked to depression. To take these findings forward, a group of Northwestern scientists led by Chetkovich, who is also director of Feinberg’s Medical Scientist Training Program, took steps in this new study to translate that insight into a potential gene therapy using mouse models.
In order to turn off HCN channel function in hippocampus neurons, the scientists surgically injected mice with a nontoxic virus engineered that expresses a gene to turn off HCN channel function. Chetkovich explained that when the HCN channels stopped working, the mice behaved like they’d been given antidepressant medications. When the opposite was tried, i.e., when the function of HCN channels were increased, the antidepressant effect disappeared.
The depression like behavior was calculated by measuring how long mice would seek to escape an environment before giving up. It is common test that is a conducted by the pharmaceutical industry to screen compounds for effectiveness as antidepressants, including medications currently on the market.
Chetkovich opined that this work is novel as it not only identifies a totally new treatment target for depression but 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.
Next, the researchers are focusing on adapting the viral gene therapy approach to human patients. They also have a grant from the National Institute of Mental Health to research on small molecules that are good candidates to be developed into oral medications to turn off HCN channels in the brain.
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