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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HD060377-03
Application #
8197067
Study Section
Special Emphasis Panel (ZRG1-F08-G (20))
Program Officer
Urv, Tiina K
Project Start
2009-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$53,942
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Gagnon, Keith T; Li, Liande; Janowski, Bethany A et al. (2014) Analysis of nuclear RNA interference in human cells by subcellular fractionation and Argonaute loading. Nat Protoc 9:2045-60
Gagnon, Keith T; Li, Liande; Chu, Yongjun et al. (2014) RNAi factors are present and active in human cell nuclei. Cell Rep 6:211-21
Gagnon, Keith T; Biswas, Shyamasri; Zhang, Xinxin et al. (2012) Structurally conserved Nop56/58 N-terminal domain facilitates archaeal box C/D ribonucleoprotein-guided methyltransferase activity. J Biol Chem 287:19418-28
Gagnon, Keith T; Corey, David R (2012) Argonaute and the nuclear RNAs: new pathways for RNA-mediated control of gene expression. Nucleic Acid Ther 22:3-16
Gagnon, Keith T; Watts, Jonathan K; Pendergraff, Hannah M et al. (2011) Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates. J Am Chem Soc 133:8404-7
Gagnon, Keith T; Pendergraff, Hannah M; Deleavey, Glen F et al. (2010) Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49:10166-78