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Taking down Down syndrome
by Kelsey Kaustinen  |  Email the author


NUTLEY, N.J.—Scientists from Roche, the University of Cantabria and Spain's Cajal Institute have published their findings on recent work with Down syndrome that highlights a potential new approach to combat the cognitive damage caused by the genetic condition. Through the use of an investigational compound, the researchers were able to selectively block specific receptors in the brain, and by so doing, reverse neurological deficits in a mouse model of Down syndrome.  
The compound in question, RO4938581, is selective for brain receptors that contain the GABA-a5 receptor subunit. When administered, the compound proved to be capable of correcting cognitive and behavioral deficits in Ts56Dn mice, as well as improving abnormalities of nerve cell number and function in adult Ts65Dn mouse brains. As an additional benefit, the improvement occurred without unwanted side effects that have historically hindered the use of non-selective GABA-A receptor blockers.  
"These preclinical results suggest that GABA-a5 receptors can be targeted for the treatment of cognitive impairment in individuals with Down syndrome resulting, at least in part, by exaggerated inhibition of neural circuits," Maria-Clemencia Hernandez, senior scientist at Roche and lead author on the paper, said in a press release.  
The compound's effects are particularly encouraging given the difficulty of balancing the inhibition of GABA. If it is entirely inhibited, Hernandez says, there are detrimental side effects such as seizures and panic attacks, among others. But through the modulation and reduction of activity the investigational compound manages, the side effects are not experienced. In addition, she notes, it "seems to be very safe."  
"What is expected is that the longer the treatment is, the more likelihood that we will see better improvement," says Hernandez.  
As for whether there is potential for this compound to prevent cognitive impairment if it is administered early in life in children with Down syndrome, Hernandez says that is what the team hopes for. Should the results seen in the animal models reflect the efficacy in humans, she says, it could be expected that there would be a higher benefit if administered during formative years "because it's the time when we are more actively learning new things, and it will help in the end to have better quality of life, learn more things, being able to be more independent later on in life."
The Global Down Syndrome Foundation notes that Down syndrome is "the least funded major genetic condition" by the National Institutes of Health, and as such, few corrective options exist. The need for such options is significant, however, as the National Down Syndrome Society estimates that one in every 691 babies in the United States are born with Down syndrome, while the World Health Organization approximates that the global incidence is between one in 1,000 to one in 1,100 live births, noting that "approximately 3,000 to 5,000 children are born with this chromosome disorder" every year.  
A related compound—RG1662, a Roche GABA-a5 Negative Allosteric Modulator (NAM)—is currently under investigation for cognitive enhancement in Down syndrome patients. The compound acts on a subset of receptors for GABA found in discrete brain regions associated with cognitive processing, where they hinder communication between nerve cells. GABA-a5 NAMs suppress GABA's action, limiting the inhibiting signals between nerve cells. The compound is the first specifically designed to ameliorate the cognitive impairment found in Down syndrome, and by targeting GABA-a5 receptor subtypes, RG 1662 is capable of targeting GABA over-activity in brain systems that are critical for learning, cognition and memory.  
In previous tests, the GABA-a5 NAM has been shown to be well tolerated in healthy volunteers, and Roche currently has a trio of early-phase clinical trials underway in Down syndrome. The trials include a study to evaluate the safety and tolerability of the investigational molecule, a non-drug study to evaluate cognition and adaptive behavior in adolescents and young adults and an imaging (PET) study to determine receptor expression and occupancy by the investigational molecule. Roche expects the Phase I studies to be complete this year.
"Our drug research in Down syndrome may offer a novel therapeutic avenue to treat the cognitive deficits in people with Down syndrome, enhance their communication skills and ultimately help them have greater independence in their daily lives," Luca Santarelli, head of Neuroscience at Roche, commented in a statement. "The development of this agent is in line with our strategy to discover new medicines that are based on a deep understanding of disease mechanisms and provide options for conditions of high unmet medical need."
The paper, "Reducing GABA-a5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of Down syndrome," appeared in the Journal of Neuroscience Feb. 27.

Code: E03271305



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