Novartis researchers find biomarker for therapy response in Fragile X syndrome
Basel – Epigenetic modifications of the FMR1 gene in Fragile X Syndrome are associated with the response to Novartis’ Phase II metabotropic glutamate receptor (mGluR5) antagonist AFQ056A, according to a study in 30 patients (Science Translat. Medicine, 5-1-2011). Fragile X is the most common known single gene cause of autism and the most common inherited cause of intellectual disability, affecting 1 in every 5,000 children worldwide. Without a cure, the syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the protein coded by the FMR1 (Fragile X Mental Retardation-1) gene, which is required for normal neural development. According to Sébastien Jacquemont and colleagues, not all of the 30 patients treated with the symptomatic therapy showed improvement, but an analysis of those that did revealed that the promoter of the FMR1 gene in those patients was fully tagged with methyl groups. The methyl group tags signalled that the FMR1 gene was completely shut off in these patients, providing a possible signature of people with Fragile X who could benefit from mGluR5-blocking drugs. The team also ran a large set of tests designed to detect changes in behaviours, such as hyperactivity and inappropriate speech in the patients. While the new drug had no effect on behaviour as measured by the first set of tests, it did show an effect on a secondary group of tests, when compared to a group of patients given a placebo treatment. Taking a closer look, the authors found that each member of the group of patients with fully methylated FMR1 promoters showed improvement in behaviour. The group with partially methylated promoters showed no such changes. This correlation between response to treatment and methylation status of the FMR1 promoter sets the stage for future studies designed to test whether methylation can serve as a predictor of positive drug response in patients with Fragile X syndrome. Novartis runs also clinical programmes with AFQ056A in Parkinson’s disease and GERD.