Activating Gene Expression with Antigene RNAs to Treat Genetic Diseases

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DESCRIPTION (provided by applicant): The common genetic diseases muscular dystrophy (MD), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) have crippling effects on childhood development. They share in common the fact that they can potentially be treated by increasing expression of a single disease-related gene. However, pharmacological activation of gene expression is not typically considered an option for therapeutic treatments due to the non-specific effects of most drugs. Recently the Corey laboratory discovered a robust and specific method for increasing expression of select genes. Small duplex RNAs, called antigene RNAs (agRNAs), are targeted to gene promoters to turn on transcription. These agRNAs actually interact with ubiquitous non-coding RNAs that span gene promoters to elicit changes in local chromatin structure, thus resulting in increased gene expression. The disease-related genes for MD, SMA and FXS all have non- coding RNAs associated with their gene promoter regions and their promoters are well-defined, important features for the successful use of agRNAs. The proposed research will fully characterize non-coding RNA transcripts that span the promoter of each disease-related gene. agRNAs will then be designed to target disease-related gene promoters and screened to identify those that can activate gene expression. Finally, key features of agRNA-mediated gene activation will be investigated to understand agRNA mechanism and help establish efficient agRNA design rules. The results of this study will lay the groundwork for developing agRNAs as novel therapeutic agents to ultimately treat debilitating genetic diseases like MD, SMA and FXS that require increased expression of specific genes. Muscular dystrophy, spinal muscular atrophy and fragile X syndrome are just a few of the many debilitating disorders that disrupt proper childhood development, resulting in a poor quality of life and dramatically shortened lifespans. Treatments for these diseases often lie in increasing the expression of select genes, which is not an option with currently available drugs. The results from this proposed research will provide evidence for antigene RNAs as potential gene-specific drugs and open the door for the first time to treatments for many diseases that require specific increases in gene expression.