Switchable mRNAs with Enhanced Translational Efficiency for Tissue-Specific Expression

Background & Unmet Need

• mRNA-based drugs provide a promising alternative for gene replacement in a broad range of diseases
• However, prolonged protein abundance following mRNA translation remains a major challenge for mRNA therapeutics, especially in highly metabolic tissues such as the liver
• The 5’-untranslated region (5’-UTR), located upstream of the coding region of a messenger RNA, plays a pivotal role in gene expression
• Large secondary structures, such as stem-loops, located upstream of the initiation codon may inhibit translation initiation by blocking cap-dependent ribosome entry
• MicroRNAs are regulatory small RNAs that bind to target mRNAs, some of which are expressed in a cell or tissue-dependent manner
• Unmet Need: Methods of enhancing mRNA expression in a tissue-specific manner, especially in metabolic tissues

Technology Overview

• The Technology: A novel design strategy for functionally switchable mRNAs that allow for tissue and cell-specific expression
• MicroRNA binding elements are incorporated in the 5’-UTR, which respond to endogenous microRNAs
• Upon binding to microRNAs, the secondary structure of the mRNA unwinds into to a linear conformation, switching mRNAs from an ‘off’ to an ‘on’ state
• The linearized conformation of the mRNA promotes translation initiation only in cells and tissues which contains the endogenous microRNA
• PoC Data: A miR-148-dependent LDLR-coding mRNA was constructed (miR-148 is a liver enriched microRNA)
• Treatment with switchable LDLR mRNA significantly reduced non-HDL cholesterol levels compared to generic LDLR mRNAs in severely hypercholesteremic male LDLR knockout mice

Technology Applications

• Targeted mRNA gene therapy for treatment of familial hypercholesterolemia or dyslipidemia
• Targeted mRNA gene therapy for other diseases caused by loss of function gene variants or which may be improved by tissue-specific gene expression
• Improved targeting of existing mRNA gene therapies

Technology Advantages

• Allows for tissue-specific translation of mRNAs
• Improves mRNA stability and translation in cells
• mRNA regulatory elements are easily incorporated into mRNA design