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Inhibiting Inhibition to Treat Down Syndrome Symptoms

By Anette Breindl
Science Editor

By targeting one specific type of inhibitory brain receptor, researchers have been able to improve neural function and memory in a mouse model of Down syndrome. The findings give additional support to the idea that some neurodevelopmental disorders can be reversed, at least partially, after they are established.

The team published their findings in the Feb. 27, 2013, issue of the Journal of Neuroscience.

"By targeting this type of receptor, we can normalize not only the cognitive deficits, but we can improve function," senior author Maria-Clemencia Hernandez told BioWorld Today.

In their work, Hernandez, who is at Roche AG, and colleagues both at Roche and in academia chronically treated mice that have an animal version of Down syndrome with RO4938581, a drug that targets GABA receptors containing an alpha5 subunit. GABA is the major inhibitory transmitter in the brain, and in Down syndrome, there appears to be too much inhibitory signaling in the hippocampus – where, it so happens, GABA receptors with the alpha5 subunit are concentrated.

Treatment began at 3 months of age, when mice are already adults. They were treated with daily doses of RO4938581, and the team tested their memory ability as well as their anxiety levels, and whether the drug made them seizure-prone.

Hernandez and her colleagues also looked at the animals' brains to see whether treatment had an effect on long-term potentiation, a form of brain plasticity that the brain uses to store memories, and on the birth of new neurons in the hippocampus.

The studies were blinded, that is, the experimenters knew neither the genotype of the animals, nor whether the animals were receiving drug or placebo. Such blinding is still unusual in preclinical experiments, although it is among the possibilities being discussed for how to improve the currently dismal reproducibility rate of animal studies. (See BioWorld Today, April 2, 2012.)

Hernandez said, though, that at Roche blinding in preclinical studies has long been the norm. "Internally, that is what we always do, because otherwise it is difficult to be confident in the data." And increasingly, the company's external collaborators, too, are conducting their experiments blinded, as was the case with the work now reported in the Journal of Neuroscience.

Treatment with RO4938581 improved the animals' memory abilities in a maze, decreased hyperactivity and reversed their long-term potentiation deficit. In the hippocampus, which is an important brain structure for memory and cognition, it also increased the birth rate of neurons back to the levels seen in normal animals, and led to a decrease in the number of inhibitory connections between cells.

Hernandez and her team also tested the compounds' effects on seizures and anxiety, two areas where side effects might crop up.

"Seizures are always a concern when you work with GABA-A receptors," Hernandez said and so, looking at seizure susceptibility is "a key experiment that we always perform." But the team did not see an increased susceptibility of the animals to develop seizures, despite the fact that some Down syndrome patients are highly prone to seizures.

It also did not increase the animals' anxiety. Anti-anxiety drugs such as Valium (diazepam, Roche AG) increase the activity of some types of the GABA-A receptor. But as with seizures, Hernandez and her team noted no ill effects of their compound on anxiety levels of the mice.

The findings give additional support to the idea that some neurodevelopmental disorders can be reversed, at least partially, after they are established. "It used to be that everybody thought the brain is fixed" in adulthood, Hernandez said. But her team's findings showed, like other recent studies have, that "it is still possible to induce plasticity" and consequently, improve function, in the adult brain. (See BioWorld Today, April 12, 2012.)

That's not to say that the compound is a cure-all for what ails those with Down syndrome, which has a multitude of symptoms, as might be expected for a condition that results from an extra copy of an entire chromosome. Almost all people with Down syndrome develop early onset Alzheimer's disease in their 30s and 40s, and Hernandez does not think RO4938581 will do anything to change that – Alzheimer's disease, she said, is "a separate issue" from the cognitive disabilities that Down syndrome patients face earlier in life.

Roche is testing an analogue compound to RO4938581, RG 1662, in three separate Phase I trials in young adults – both healthy volunteers and individuals with Down syndrome. The company expects to complete those studies in 2013.