CRISPR Technology To Help Solve Depression

About 14 percent of Americans take antidepressant drugs for depression, anxiety, chronic pain or sleep problems. For the 15 million Americans who have clinical depression, roughly 40% do not find relief with antidepressants.



Researchers at Washington University School of Medicine in St. Louis and Sage Therapeutics in Boston are trying a different approach to alleviate depression. Most antidepressant drugs target serotonin receptors, aiming to boost serotonin, a chemical thought to regulate mood and social behavior. Using CRISPR technology, the scientists have been able to target an altogether different type of receptor called delta-type GABA receptors. They think that natural mood-boosting substances in the brain can target these receptors.

Principal investigator Steven Mennerick, professor of psychiatry told Thailand Medical News. "There's a real need to develop more effective antidepressants.The most commonly prescribed antidepressant drugs such as Prozac, Paxil and Zoloft were approved by the FDA more than 30 years ago, and there's been a dearth of new antidepressants  since then. A completely new approach is warranted."

The new approach involves targeting GABA receptors with substances called neurosteroids, chemicals that occur naturally in the brain and are involved in emotional and motivational brain networks. "Neurosteroids are thought to selectively interact with delta-type receptors, and there's evidence that those drugs may help patients suffering from depression," said Mennerick, who also is the scientific director of the Taylor Family Institute.

There is an "alphabet soup" of GABA receptor subtypes on brain cells. Targeting the delta-type GABA receptor could help alleviate depression because GABA, an inhibitory neurotransmitter, may help slow down some of the cognitive processes that lead to overwhelming and negative thoughts and feelings. Some types of GABA receptors have been linked to anxiety, but although many scientists have looked at the receptors as potential targets for depression, developing compounds that selectively bind to specific types of GABA receptors has complicated the search.

Mennerick and his colleagues focused on GABA receptors located on neurons in the brain's hippocampus, a part of the brain involved in learning and memory. Using CRISPR, they mutated the delta-type GABA receptors to isolate and test their role in brain functioning.

Earlier studies involving Taylor Family Institute scientists and carried forward in human trials by Sage Therapeutics suggested that targeting these receptors could alleviate symptoms of depression in women suffering from severe postpartum depression .

In 2018, the Lancet published results of a Sage-funded trial of the neurosteroid brexanolone as a treatment for postpartum depression. The study of 21 women showed that depression improved significantly in those given the drug. 

"The drugs affect GABA receptors, but they also seem to have anti-inflammatory properties.We think it may be that special mix of reducing inflammation while activating these receptors that contributes to antidepressant effects." said Dr Mennerick to Thailand Medical News.

"It's very difficult to differentiate among different types of GABA receptors because they share so many common properties. Previously, scientists really had no way to isolate the subtypes, but we can do that with CRISPR/Cas9 gene editing technology to learn how particular drugs affect individual receptor subtypes."he further added.

Mennerick explained that if further studies confirm that activating delta-type receptors has antidepressant effects, a next step would be to develop and test more compounds that activate those receptors. He said the mutant mice give them the tool they need to develop more potent drugs that also are more selective, with fewer side effects.

"We have a catalogue of neurosteroid compounds that our colleagues have been developing over the last 20 years, and any one of them could prove to be an effective antidepressant," he said. "If brexanolone works in postpartum depression mainly through these delta-type receptors, then it may work in other types of depression, too. Eventually, the goal would be to develop ever more potent and selective drugs to interact with those same delta-type receptors."

Updates:

Along with Sage Therapeutics, the Taylor Family Institute has moved that strategy forward with a neurosteroid drug that was shown to be effective in a recent clinical trial. Studying 89 patients 45 of whom were randomly chosen to receive a neurosteroid called SAGE-217, while the other 44 received an inactive placebo, researchers found that the investigational drug reduced symptoms of depression in less than two weeks. The results were published recently in the New England Journal of Medicine.

Dr Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, directs the Taylor Family Institute and was one of the authors on the recent publication. He said the speed at which SAGE-217 is heading toward clinical use is remarkable. Another neurosteroid drug developed by Sage already has been approved for clinical use. The intravenous drug Zulresso (brexanalone) was approved by the Food and Drug Administration in March to treat women suffering from serious postpartum depression. Zorumski described the ongoing development of neurosteroids to treat depression and possibly other psychiatric illnesses.

“The neurosteroid drug for postpartum depression was the first new antidepressant to come to market in years. First, the investigational drug SAGE-217 is a proof of concept that you can develop an oral neurosteroid drug to treat men and women with major depression. That's a big deal. Secondly, the drug is given once daily, with a dose of 20 to 30 mg per day, so patients don't have to take multiple pills each day, which can be the case with other antidepressants. And third, we were excited to see how quickly the drug alleviated symptoms. Patients were doing better in the first few days on the drug. After a week on the drug, they were clearly distinguished from those taking a placebo, and then they continued to improve over 14 days. When the drug was stopped after two weeks, patients maintained the benefit from the drug for almost another 30 days, which was as long as the study lasted. The fact the drug was effective in a two-week trial, that it worked so quickly and that its effects apparently persist is unusual in psychiatry. That's different from any of the other oral drugs now available for depression.” Commented Dr Charles F. Zorumski to Thailand Medical News.

This particular drug is a Sage Therapeutics compound, but it was based on a technology platform developed at Washington University. Doug Covey, the Andrew C. and Barbara B. Taylor Distinguished Professor of Psychiatry, has developed more than 700 neurosteroid compounds in his lab. The university licensed that library of compounds to Sage, and those molecules became the basis for what the company developed. Although SAGE-217 is not one of the hundreds of compounds developed here, there is a joint Washington University-Sage compound that is progressing toward clinical trials now, and we believe other promising compounds soon may be in the pipeline.

The drugs are mildly sedating. They interact with GABA receptors in the brain. GABA is the major inhibitory neurotransmitter in the brains of all mammals, so an agent that augments GABA can be sedating. In fact, the biggest challenge with brexanalone for postpartum depression is the potential for excessive sedation. Sleepiness also affected some of the patients who took SAGE-217, but that's not necessarily bad because sleep disturbances are a big problem in depression and in a range of psychiatric illnesses. The drug may relieve depression at lower doses, without causing the sedation that was seen in some patients in the clinical trial, but that needs to be tested.

“Our work at Washington University opened eyes to the potential uses of neurosteroids and how the chemical structure of these steroids influences their activity. Initially, nobody thought these naturally occurring molecules would make good drugs because many were vulnerable to being broken down in the body so that they never would make it to the brain. When our early neurosteroid research looked promising, we proposed the strategy to various pharmaceutical companies. Sage was formed in 2010, with Doug Covey as a co-founder of the company. I have served on the company's scientific advisory board and have been involved in discussions about mechanisms of action and which clinical trials should be designed.For example, when I saw the data for the postpartum drug brexanalone, I would point out that the aim wasn't only to treat postpartum depression but that neurosteroids potentially had broader uses. Those included clinical depression. in men and women, anxiety and treatment-resistant depression. And as early data first came in on the latest drug, SAGE-217, it became clear that it could be effective in men and women with depression and that we probably should study it further in patients with treatment-resistant depression. That's our plan here at the Taylor Family Institute: to evaluate neurosteroids in patients whose depression has not been relieved by other drugs because that's where we could see the greatest impact.” He further added.

References:

a) Trial of SAGE-217 in Patients with Major Depressive Disorder ,Handan Bruce, M.D., 
Christopher Silber, M.D., Inder Kaul, M.D., Haihong Li, Ph.D., Robert Lasser, M.D., Charles F. Zorumski, M.D., et al. N Engl J Med 2019; 381:903-911 DOI: 10.1056/NEJMoa1815981
 
b) Min-Yu Sun et al. Chemogenetic isolation reveals synaptic contribution of δ GABAAreceptors in mouse dentate granule neurons, The Journal of Neuroscience (2018). DOI: 10.1523/JNEUROSCI.0799-18.2018
 
c) Stephen Kanes et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial, The Lancet (2017). DOI: 10.1016/S0140-6736(17)31264-3