About Fragile X Syndrome
Fragile X syndrome is the most common inherited cause of autism and intellectual disabilities. It affects people of all races and ethnicities, and has a higher incidence among males (1 in 4,000) versus females (1 in 6,000).
Fragile X syndrome is caused by a mutation in a gene known as FMR1. In the body FMR1 manufactures a protein known as FMRP that is essential for normal cognitive development. Each FMR1 gene contains a series of copies of two components of DNA, cytosine and guanine, presented in a specific sequence. The amount and usability of FMRP, in part, determine how severe the effects of fragile X will be.
The number of repeated sequences of this specific series of cytosine and guanine in the FMR1 gene varies from person to person. In healthy people who do not have the fragile X mutation, this series typically repeats between six and 40 times, with the average being about 30 repeats. In people with a mutated FMR1 gene, the sequence of cytosine and guanine may be repeated hundreds of times. When this occurs, the gene can be inactivated, making it unable to produce FMRP in sufficient quantities or at all.
Fragile X syndrome is a chronic disease with cognitive and neuropsychiatric symptoms including learning and memory deficits, hyperactivity, social anxiety, mood liability and other autistic behaviors. Physical features associated with fragile X syndrome include large and protruding ears, a long face and low muscle tone. When patients exhibit these symptoms, DNA testing is typically used to confirm a diagnosis.
There are currently no FDA-approved drugs indicated for the treatment of fragile X syndrome. Anticonvulsants, atypical anti-psychotics, SSRIs and stimulants are sometimes used to help manage symptoms of this disease.
Recent studies suggest that extracellular signal-regulated kinase (ERK) plays a critical role in synaptic plasticity (the ability of certain synapses to strengthen or weaken over time) and neurodevelopment. Fragile X syndrome is associated with increased activity of the Ras-extracellular signal-regulated kinase pathway (Ras-ERK), which can lead to abnormalities in neuronal connections. AMO-01 is an inhibitor of the Ras-ERK pathway. In pre-clinical efficacy studies, AMO-01 has been shown to rescue the neuronal phenotype of the FMR1 knockout in transgenic mouse models of fragile X syndrome. This provides strong scientific evidence to support the conclusion that inhibition of the Ras-ERK cascade may have therapeutic benefit in the treatment of fragile X syndrome in humans.
Wang, Zhu et al. 2012. J. Neurochemistry. 212(121), 672-679.