CONTEXT

Fragile X-Syndrome (FXS) is the most common cause of inherited mental retardation and affects 1 in every 2000 men and 1 in every 4000 women, together representing nearly 500,000 persons in Europe and USA. This disease is caused by 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 (Fragility Mental Retardation 1) gene.
In normal individuals, FMR1 is a RNA-binding protein that is believed to regulate the transcription and translation of a substantial population of mRNA, and it plays important roles in learning and memory. It also appears to be required for normal neural development since it is involved in development of axons, formation of synapses, and the wiring and development of neural circuits. Its mutation leads to its silencing, and results in a spectrum of characteristic physical and intellectual limitations, as well as emotional and behavioral features which range from severe to mild in manifestation.
To date, there is no cure for the Fragile X-Syndrome and current therapeutic strategies rely on behavioral therapy, special education, and when necessary, treatment of physical abnormalities. 

TECHNICAL DESCRIPTION

It has recently been shown that the silencing of FMR1 is leading to a 50% reduction of the level of KCNMA1, the sub-unit of the large-conductance Ca2+ and voltage-activated K+ (BKCa) channel (Liao et al., PNAS 2008). BKCa channels have a tetrameric structure, each monomer of the channel-forming alpha subunit being the product of the Kcnma1 gene, and this reduced level of KCNMA1 protein results in a fonctional impairment of the channel activity. BKCa channels are expressed in almost every tissue in our body and participate in many critical functions such as neuronal excitability, determination of action potential duration and frequency, neurotransmitter release and vascular tone regulation.
Using the BKCa channel opener BMS204352, the inventors have been able to restore a normal BKCa channel activity in a FXS patient cell culture in a similar manner than what they observed in lymphoblastoid cultures of an autistic patient with a de novo 9q23/10q22 translocation (Laumonnier et al. Am J Psychiatry 2006). In addition, they showed that BMS-204352  restores dendritic spines maturation of Fmr1 KO neurons (4h treatment).
Working with fmr1-KO mice, the FXS animal model, Dr Briault and Dr Perche have now shown that BMS204352 allows behavioral recovery in a surprisingly efficient manner when administered in 1 injection i.p 2mg/kg:

• Direct social interaction test showed a wild-type social interaction phenotype,
• Social preference test showed a wild-type social preference phenotype,
• Elevated plus-maze test showed a wild-type level of anxiety,
• Y-maze test a wild-type spatial recognition (work memory).

The quantification of cerebral metabolites (hippo/cortex) using Magnetic Resonance Spectroscopy (MRS) demonstrated that BMS-204352 (1 injection i.p 2mg/kg) restores the normal synaptic function. 

DEVELOPMENT STAGE

Interestingly, BMS204352 has been clinically developed by Bristol-Myers Squibb up to Phase III before it failed to improve stroke’s issue, and therefore has an excellent ADMET profile (the whole regulatory package, results and samples have been obtained from BMS). The molecule is now free to operate.

The research team is now strengthening preclinical data and setting up a clinical trial. As a medical geneticist, Dr Briault has established close relationships with hospitals and with French and international patient associations that are active in the field of Fragile-X syndrome research and support and/or collaborate to his action.
An orphan drug designation filing is ongoing. CNRS is willing to collaborate with and license this patent to a pharmaceutical company, preferably experienced in the clinical development and marketing of rare disease treatment, to achieve the development of this drug. Indeed more than 1,5 million people may receive this life-long treatment, with a possible indication extension to all mental retardation associated with BKCa anomaly.

For further information, please contact us (Ref 04388-01)