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Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome

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Annual rept. 1 Aug 2014-31 Jul 2015

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Fragile X syndrome FXS is the most common heritable form of intellectual disability, the most common single-gene form of autism, anda relatively common cause of epilepsy. The syndrome is caused by partial or complete silencing of the fragile X FMR1 gene when a CGG-repeat element in the gene expands to more than 200 repeats, leading in turn to loss of the FMR1 protein FMRP. The protein is important for brain development, and its loss is accompanied by both intellectual and behavioral disability. Accordingly, the central objective of the proposed research is identification of therapeutic agents that stimulate production of FMRP from residual FMR1 messenger mRNA in neurons, thereby reversing the effects of decreased gene activity. Our approach is twofold i to block repressive interactions between microRNAs and the 3 non-coding portion of the FMR1 message, thereby leading to increased protein levels ii to screen a large library 20,000 compounds of small molecules, each having the potential for crossing the blood-brain-barrier, for those with the ability to increase FMRP levels. Increasing the expression of FMRP holds the potential to correct ALL of the clinical domains of fragile X syndrome, including epilepsy-like activity observed for both those with FXS and carriers of smaller CGG-repeat expansions. Finally, posttraumatic stress disorder PTSD has been described in fragile X syndrome and in premutation carriers. Thus, the proposed studies may lead to treatments that reduce the PTSD risk as well, an issue of importance for the military personnel. Since the prevalence of fragile X syndrome is approximately 1 in 3,000 to 4,000 in the general population, nearly two-thousand children of service personnel are likely to have fragile X syndrome, with a much larger number 7,500 of active military personnel being carriers of an expanded premutation form of the FMR1 gene.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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