NUTLEY, NJ -- February 27, 2013 -- Today, Roche scientists, along with scientists at the University of
Cantabria and Spain’s Cajal Institute, report findings in the Journal of Neurosciencea
, which demonstrate that by selectively blocking specific receptors in the brain they were able to reverse key neurological
deficits in a mouse model of Down syndrome (the Ts65Dn mouse). Using an investigational compound
(RO4938581) selective for brain receptors that contain the GABA-A a5 receptor subunit, Roche scientists
and their collaborators corrected cognitive and behavioral deficits in Ts65Dn mice. They also showed that
treatment with RO4938581 improved abnormalities of nerve cell number and function in adult Ts65Dn
mouse brains. Together, these data demonstrate that selectively modulating GABA-A receptors in key
regions of the brain results in major cognitive and behavioral improvements. These positive findings
occur without unwanted side effects that have limited the use of non-selective GABA-A receptor blockers.
“These preclinical results suggest that GABA-A 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,” said Maria-Clemencia Hernandez, Senior Scientist at Roche and lead author on the
A Roche GABA-A a5 Negative Allosteric Modulator (NAM) is currently being studied for cognitive
enhancement in individuals with Down syndrome. The compound (RG 1662) acts on subset of the
receptors for the chemical messenger GABA that are present in discrete brain regions associated with
cognitive processing where they inhibit communication between nerve cells. GABA-A a5 NAMs suppress
the action of GABA thus reducing the inhibitory signals between nerve cells in brain regions important
for cognitive functions.
RG 1662 represents the first compound specifically designed to improve the cognitive impairment
associated with Down syndrome, which is believed to result from excessive inhibition of specific brain
circuits. By targeting GABA-A a5 receptor subtypes, the compound possesses a unique pharmacology that
enables the targeting of GABA over-activity mainly in brain systems that are important for cognition,
learning and memory. The final objective is to safely reset the balance between inhibition and excitation
in brain systems that are altered in Down syndrome.
“Our drug research in Down syndrome may offer a novel therapeutic avenue to treat the cognitive
deficits in people with Down syndrome, enhance their communications skills and ultimately help them
have greater independence in their daily lives,” said Luca Santarelli, Head of Neuroscience at Roche. “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.”
About Down syndrome
Down syndrome is one of the most common chromosomal abnormalities. It affects around one in 650 to
1,000 live births. Worldwide some 30,000 babies are born with Down syndrome each year. People with
Down syndrome have a wide range of abilities but the majority have cognitive deficits which can lead to
challenges with independence in their daily activities, education and employment. At present, there are no
treatment options that address the cognitive impairments associated with Down syndrome. Therefore,
new treatments that improve cognitive skills and help people with Down syndrome adapt and function
better in their environment, may offer them a greater degree of independence.
To date, Roche’s GABA-A a5 NAM has been tested in healthy volunteers and was shown to be well
tolerated. Roche is conducting three early phase clinical trials in the area of Down syndrome. One
examines safety and tolerability of the investigational molecule, the second is a non-drug study to evaluate
cognition and adaptive behavior in adolescents and young adults and the third is an imaging (PET) study
to assess receptor expression and occupancy by investigational molecule. Roche expects to complete Phase
I studies in 2013.
Roche is working on new molecular entities in neuroscience that could become the next generation of
medicines for a range of diseases including schizophrenia, multiple sclerosis, depression,
neurodevelopmental disorders, Parkinson’s disease and Alzheimer’s disease. With one of the strongest
neuroscience pipelines in the industry, and by working closely with academic institutions, biotech
companies, and forming public-private partnerships, Roche’s focus is on expanding its neuroscience
franchise to better serve patients.
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined
strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company, with truly
differentiated medicines in oncology, infectious diseases, inflammation, metabolism and neuroscience.
Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a
frontrunner in diabetes management. Roche’s personalised healthcare strategy aims at providing
medicines and diagnostic tools that enable tangible improvements in the health, quality of life and
survival of patients. In 2012 Roche had over 82,000 employees worldwide and invested over 8 billion Swiss
francs in R&D. The Group posted sales of 45.5 billion Swiss francs. Genentech, in the United States, is a
wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical,
Japan. For more information, please visit www.roche.com or www.roche-nutley-com.
Reducing GABAA a5 receptor-mediated inhibition rescues functional and neuromorphological deficits in
a mouse model of Down syndrome, February 27, 2013 – 33(9):
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