Roche research sheds light on improving neurological deficits in mouse model of Down syndrome
Results could have implications for individuals with Down syndrome
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 Neuroscience, 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 α5 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 α5 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 publication.
A Roche GABA-A α5 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 α5 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 α5 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 α5 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 α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of Down syndrome, February 27, 2013 – 33(9): http://www.jneurosci.org/content/33/9/3953.abstract?etoc
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