Scientific insights into brain chemistry trigger drug trials for Down syndrome

Luca Santarelli, Roche's head of neuroscience

Just about a year ago Roche scientists working under neuroscience leader Luca Santarelli published some intriguing data from a mouse study which demonstrated that by blocking the chemical GABA in key regions of the brain they were able to trigger major cognitive and behavioral improvements in a model for Down syndrome. Now Roche ($RHHBY) is prepping for a human study to see if one of their GABA inhibitors can help boost the IQ of young people with Down syndrome, recruiting 180 patients, according to a report from Bloomberg. And a small biotech inspired by the work of Stanford University investigator Craig Garner is taking the same approach in the clinic with a drug dubbed BTD-001.

Bloomberg writer Robert Langreth talked with Garner, who says he woke up to the potential of restoring more normal neural circuitry when he tested the GABA-blocking drug PTZ on mice. "It was bloody amazing," Garner told Bloomberg. "It was shocking how well it worked."

But after trying, and failing, to get some Big Pharma interest in a long neglected field, Garner started Balance Therapeutics in 2009. Lyndon Lien, the company CEO, tells Bloomberg that he expects to see results from a 90-patient study in about a year. Roche's work, meanwhile, has been spearheaded by senior scientist Maria-Clemencia Hernandez.

"We are currently about to launch a Phase II trial investigating our experimental medicine RG1662, a highly selective GABA-A a5 Negative Allosteric Modulator, in individuals with Down syndrome," a spokesperson for Roche's pRED division tells FierceBiotech in an email. "The trial will recruit 180 individuals with Down syndrome aged 12-30 across 10 countries. Our ultimate goal is to enable individuals with Down syndrome [to] live a more independent life." 

RG1662 was designed to improve the cognitive impairment brought on by "excessive inhibition of specific brain circuits," Roche adds. "The unique pharmacology of our investigational drug RG1662 addresses the imbalance of excitatory and inhibitory neurotransmission: based on animal models, an imbalance between excitatory and inhibitory neurotransmission in the brain is believed to be the underlying cause of the cognitive deficits in individuals with Down syndrome." 

The research work has captured the attention of some leading practitioners in the field, who have been excited by the life-transforming impact a 10- or 15-point increase in IQ could have on someone who suffers from Down syndrome. And the fresh hope for an improvement marks a major shift for parents and patients who had little to look forward to just a few years ago.

"Ten years ago if you told anyone there were going to be trials of drugs to improve cognitive symptoms of Down syndrome they would have laughed you out of town," Johns Hopkins geneticist Roger Reeves tells Bloomberg. The advances "in just the last 5 years are truly amazing."

Reeves is in a good position to know. He's been doing research of his own on improving cognition, reporting last fall that turbocharging the sonic hedgehog pathway in the developing minds of mice at birth could prove to be another promising approach to Down syndrome. The research in this field is still clearly at a very early stage, a stage of development known for extraordinarily high risk and frequent failures. But new discoveries about how the brain works could one day lead to some life-changing therapies for a disease once written off to fate. And the work could have implications for autism as well.

- here's the article from Bloomberg