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It’s a well-known messenger in the brain: a neurotransmitter dubbed GABA that mellows us out. Drug developers have been tinkering with it for decades, and they’ve scored some big hits, notably Xanax and Valium.

Now, they’re reaching for even bigger targets. A flurry of startups are working to target the GABA pathway with more precision than ever before, hoping to come up with medications that can treat a range of neurological disorders and mental illnesses.

It’s all early stage, far from ready for prime time — and at least one much-touted GABA project has flopped — but scientists express hope that tinkering with the GABA pathway could potentially increase IQ in people with Down syndrome, improve cognition in patients with Alzheimer’s, and offer quick relief to women struggling with postpartum depression. Such drugs might even treat autism.


“I think we can modulate brain activity in a way that hasn’t been done before,” said Jeff Jonas, the CEO of Sage Therapeutics in Cambridge, Mass.

“The centrality of the role of GABA has long been known, so it’s been an attractive target,” said Sharon Rosenzweig-Lipson, vice president of research and development at Baltimore-based AgeneBio.


The most commonly used drugs that impact the GABA pathway are “benzos” — an effective but often addictive class of psychoactive medications that include anti-anxiety, anti-seizure, and muscle relaxant drugs like Valium, Klonopin, Ativan, and Xanax.

Drugs that target the GABA pathway have traditionally worked as on/off switches. Agonists, which excite the flow of this neurotransmitter, wind up working as sedatives. Antagonists, which inhibit GABA from firing in the brain, can be used as stimulants.

The new wave of GABA drugs, by contrast, work as modulators. They target only certain receptors, which lets drug makers more delicately balance the flow of the neurotransmitter in the brain. It’s the difference between slamming down your hands on piano keys all at once and picking out a careful melody.

“The effects of these drugs can be fine-tuned, because they bind to some receptors, but not others,” said Arthur Simen, who is leading a GABA drug discovery program at Pfizer, working on medications for  epilepsy and pain.

Here’s a look at a few of the biotechs working in this field:

Positive signs for postpartum depression

Sage Therapeutics recently reported some exciting — but very early — data from a 21-patient clinical trial that used a GABA modulator to ease symptoms in women with postpartum depression.

The company’s foray into postpartum depression was fairly speculative, Jonas said: Sage basically went looking for any acute illnesses where there was a change in GABA function.

In postpartum women, the level of a brain chemical called allopregnanolone has been found to drop. That chemical modulates the GABA pathways. So the Sage team speculated that if they could create a molecule that replaced allopregnaolone, “we would see a rapid and complete response” in the form of a stabilized mood, Jonas said.

“We all recognize that GABA is a very potent mechanism,” he said.

The company is also testing a GABA modulator as a treatment for epilepsy, which is also linked to misfirings in the GABA pathway.

Targeting memory loss

Johns Hopkins University spinout AgeneBio is targeting a GABA receptor, called alpha-5, that’s particularly concentrated in the hippocampus region of the brain. A hyper hippocampus has been linked to conditions like autism, memory loss, and schizophrenia.

“When the hippocampus becomes overactive, it causes memory impairment, and further neurodegeneration of the brain,” said Rosenzweig-Lipson, who heads up AgeneBio’s GABA program.

So AgeneBio is developing a GABA modulator that could slow down the over-firing of the hippocampus — and, hypothetically at least, improve the symptoms of a range of neurodegenerative diseases. It’s still conducting preclinical work, but the company plans to file paperwork that would allow it to enter clinical trials this year.

Aiming for new epilepsy treatments

Pharma giant Pfizer is targeting the GABA pathway as well: It’s in mid-stage clinical trials with experimental GABA drugs to treat lower back pain and epilepsy.

One of the biggest benefits of developing a more fine-tuned approach to GABA modulation? Because these drugs only influence a handful of receptors, instead of all them, it could be possible to give patients a higher dose with fewer adverse effects.

“With benzodiazepines, what’s limiting the dose is the adverse effects,” said Simen, who leads the research program for Pfizer. “The basic idea would be that these new GABA drugs would be safer and more tolerable because they don’t have the side effects of the benzos — the sleepiness, or the impairment of the ability to drive a car.”

Other companies testing the waters include New York-based Ovid Therapeutics, which is developing a drug called gaboxadol to treat patients with two very rare, inherited neurological diseases, Angelman syndrome and Fragile X syndrome.

Stanford spinout Balance Therapeutics, meanwhile, is using a GABA antagonist — that is, a drug that lessens GABA activity, and therefore perks people up — as a way to potentially increase cognitive skills in patients with dementia or Down syndrome.

A high-profile flop

While the field has generated considerable excitement, there have also been some high-profile failures.

Israel’s BioLineRx was readying itself in 2009 for a schizophrenia blockbuster. It had shown positive mid-stage results for what it described as a GABA-enhanced antipsychotic that could improve cognition in patients and optimistically projected scooping up 20 to 30 percent of the growing schizophrenia market.

In 2013, however, BioLineRx shut down further clinical trials of the drug, known as BL-1020. It simply didn’t work as expected.

Dr. David Lewis, chair of the University of Pittsburgh psychiatry department, studies the link between GABA and schizophrenia. While he said there’s “no question” in his mind that something goes awry with the GABA pathway in schizophrenia, the basic understanding of the disease still isn’t quite advanced enough to develop new therapies, he said.

“My sense is I think we’re kind of in a holding pattern right now,” Lewis said.

Overall, though, Lewis said he sees promise in the field of GABA modulation, because the new class of drugs can hit specific targets in the brain at a specific time. That, he said, is “an exciting thing in terms of drug development.”