Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome
Abstract
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 (m)RNA 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2015
- Accession Number
- ADA624238
Entities
People
- Isaac N. Pessah
- Paul J. Hagerman
Organizations
- University of California