Synthetic modified RNA and uses thereof
Inventors
Zangi, Lior • HADAS, Yoav • Sultana, Nishat
Assignees
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Publication Number
US-12606822-B2
Publication Date
2026-04-21
Expiration Date
Abstract
The present application relates to a nucleic acid molecule comprising a first nucleic acid sequence comprising at least a portion of a 5′ untranslated region (5′ UTR) of a carboxylesterase gene and a second nucleic acid sequence encoding a protein of interest, where the second nucleic acid sequence is heterologous to and operatively coupled to the first nucleic acid sequence. Also disclosed are methods of expressing a protein of interest in a target cell, methods of treating subject for cardiac ischemia or hepatic ischemia, and methods of identifying a nucleic acid sequence capable of selectively enhancing translation of a heterologous protein of interest in a target cell.
Core Innovation
The disclosed invention provides nucleic acid molecules and pharmaceutical compositions for administering modified mRNA (modRNA) in an ischemia-targeted manner. The approach uses a first nucleic acid sequence comprising at least a portion of a 5′ untranslated region (5′ UTR) of a carboxylesterase gene, specifically carboxylesterase 1D (Ces1D) or carboxylesterase 1 (CES1), operatively coupled to a heterologous second nucleic acid sequence encoding a protein of interest.
The invention addresses selective increase of modRNA translation under disease or context-specific conditions, including ischemic conditions. It describes a screening and identification strategy using transcriptome and proteome analysis to compare disease versus non-disease samples and to select genes where mRNA levels are similar to or low, but protein levels are higher, supporting disease-selective translation of the heterologous protein of interest.
Using the identified disease-selective 5′ UTRs, the document reports that the Ces1d 5′ UTR, including RNA Element D, selectively increases modRNA translation under ischemic conditions. The document includes comparative findings across ischemic contexts, including myocardial infarction and ischemic liver, and distinguishes performance of Element D versus the Ces1d 5′ UTR.
Claims Coverage
The coverage focuses on a nucleic acid molecule constructed from a Ces1D or CES1 5′ UTR sequence operatively coupled to a heterologous protein-of-interest encoding sequence. Four inventive features are identified.
Ces1D or CES1 5′ UTR sequence as first nucleic acid portion
A first nucleic acid sequence comprising at least a portion of a 5′ untranslated region (5′ UTR) of a carboxylesterase gene, wherein the carboxylase is a carboxylesterase 1D (Ces1D) or a carboxylesterase 1 (CES1).
Heterologous operatively coupled protein of interest coding sequence
A second nucleic acid sequence encoding a protein of interest, wherein the second nucleic acid sequence is heterologous to and operatively coupled to the first nucleic acid sequence.
Modified mRNAs as the nucleic acid sequences
The nucleic acid molecule wherein the first and second nucleic acids are modified mRNAs (modRNAs).
Pseudouridine or methylpseudouridine in modRNAs
The nucleic acid molecule wherein the modRNAs contain pseudouridine or methylpseudouridine.
The independent claim is directed to a nucleic acid molecule that combines a Ces1D/CES1-derived 5′ UTR portion with a heterologous protein-of-interest coding sequence operatively coupled to that 5′ UTR portion, with modRNA-related refinements in dependent claims.
Stated Advantages
Selectively enhances translation in ischemic heart and ischemic liver but not ischemic kidney.
Selectively increases modRNA translation under ischemic conditions.
Shows increased modRNA translation in vitro cardiomyocytes under ischemic conditions.
Shows increased in vivo luciferase signals post-myocardial infarction.
Documented Applications
Treating cardiac ischemia and hepatic ischemia.
Treatment in connection with myocardial infarction (MI).
Use in ischemic conditions including myocardial infarction (MI), including assessing post-MI luciferase signals.
Use in ischemic liver and ischemic kidney comparisons for translation effects.
Use for disease-selective translation of a heterologous protein of interest using a 5′ UTR from a carboxylesterase gene (Ces1D/CES1) and RNA Element D.
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