Roche announced the publication of a study demonstrating that chronic treatment of a mouse model of Fragile X syndrome with the novel, potent and selective Roche mGlu5 antagonist CTEP corrects a broad range of major phenotypes of the disease. The study “Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice” will be published in Neuron.
The Roche study shows that chronic treatment for a period of 1-4 months starting after disease onset in an adult mouse model fully reverses key phenotypes of Fragile X syndrome including cognitive deficits, hyperactivity, an increased susceptibility to seizures, and altered brain morphology. The study results corroborate the ‘mGlu receptor hypothesis of Fragile X’ elaborated by Mark Bear, which postulates beneficial therapeutic effects of mGlu5 inhibition in Fragile X.
“The most important implications of this study are, first, that many of the synaptic disturbances seen in Fragile X syndrome do not appear to cause an irreversible disruption of brain development, and second, that small molecule therapies targeting mGlu5 offer widespread therapeutic benefit even when administered well after symptom onset,” comments Mark Bear, Picower Professor of Neuroscience at Massachusetts Institute of Technology.
Previous studies showed that the disease onset can be prevented in mice when the mGlu5 receptor is inhibited by genetic manipulations which are effective from early embryonic development onwards. Other studies using short-duration treatment with mGlu5 antagonists reported beneficial effects for certain phenotypes. The important new conclusion reported in the Roche study is that treatment with an mGlu5 antagonist starting in adulthood can achieve a comprehensive reversal of the fully developed Fragile X phenotype in mammals. The data suggests that chronic treatment with uninterrupted drug exposure is critical for an effective treatment which has become possible due to the unique long half-life of CTEP.
“These results and especially the breadth and the magnitude of the treatment effects are very encouraging for our ongoing clinical trial investigating the Roche mGlu5 antagonist RG7090 in adult and adolescent Fragile X patients” said Luca Santarelli, Head of Roche Neuroscience. “These new preclinical data represent a paradigm shift in the way we view the treatment of Fragile X. So far, it was believed that the treatment of this condition would be mainly limited to symptomatic therapy. The new data suggest that pharmacological therapy with an mGlu5 antagonist– even if started after the disease onset – might have the potential to improve core symptoms of the disease, thereby providing a potential disease-modifying treatment for Fragile X syndrome.”
“Our current objective is to investigate whether these preclinical findings can be translated into clinical benefits for patients. To this end we plan to test RG7090 (RO4917523)in Fragile X patients through a wide age range, and explore biomarkers to identify those patients who are more likely to benefit from this treatment,” said Santarelli.
Date: April 10, 2012
Filed Under: Drug Discovery