Tethered mRNA Amplifier: A Novel Approach to Increase Protein Expression.

Posttranscriptional RNA modification has become a revolutionary clinical tool to improve the underlying condition in genetic disorders. The cell achieves translational regulation through sequence and/or structural elements that recruit specific positive- or negative-acting factors to mRNAs. Targeting mRNA expression offers a less invasive therapeutic approach than other well-known gene therapy approaches. We have utilized our understanding of mRNA translational regulation to develop a novel disease-modifying treatment called the "Tethered mRNA Amplifier." Specifically, our approach forces a key positive-acting mRNA regulator, polyadenosine binding protein (PABPC1), to bind and remain resident on the target mRNA. This enhances the target mRNA's expression precisely and restores deficient protein levels to normal. This approach effectively increases the steady-state expression level of several transcripts associated with haploinsufficiency disorders in cell culture.