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Fig. Targeting specific sequences and cis-acting elements (structures) within 5'UTR can lower Gibbs energy-dependent secondary structure formation and enhance of protein translation. Patent: Master Adam. Nucleic acid molecule designed for selective enhancement of protein synthesis. Patent no. PL237080B1, 2010.
Targeting 5′ UTRs of mRNA can enhance protein translation of selected transcripts.
Targeting 5′ UTRs of mRNA can enhance protein translation of selected transcripts.
This concept was used in the study: A Novel Method for Gene-Specific Enhancement of Protein Translation by Targeting 5'UTRs of Selected Tumor Suppressors, 2016, cited by Roche's patent:
Johannes Braun, Ross Cordiner, Lukasz Kielpinski, Soren V Rasussen, Disa Elisabet Tehler. Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. Antisense oligonucleotide. WO2023111337A1, 2022.
See more: PATENTS
Fig . Gene expression regulation by trans-acting factors targeting cis-acting elements.
The Upper panels show an mRNA 5' UTR (blue line) with functional cis-acting elements (regulatory interacting domains of the sequences) known to inhibit protein translation (green), which can be enhanced by using synthetic trans-acting factors such as dGoligos (here dG1, dG4) -designed to target these elements and minimize Gibbs energy-dependent secondary structure formation of 5'UTRs. The Lower panel shows several possible ways to regulate gene expression, including dGoligos (dG1, dG4), also known as eRNA, described for the first time in this paper. For more details see the paper.
Ways to enhance protein translation by reducing Gibbs energy–dependent secondary structure formation.
Ways to enhance protein translation by reducing Gibbs energy–dependent secondary structure formation.
Both sense and antisense oligonucleotides (SSO, ASO) have been shown to enhance translation by targeting the 5′ UTRs of selected transcripts. Moreover, both synthetic and naturally occurring microRNAs targeting 5′ UTRs can also enhance translation; however, the underlying mechanisms remain to be elucidated. The concept has since been cited and extended in industrial innovation, including Roche’s patent WO2023111337A1 (2022) and Ionis Pharmaceuticals’ patent EP3313989B1 (2024), underscoring its international recognition and translational relevance. Notably, Roche applies this strategy using antisense oligonucleotides (ASO) targeting the 5′ UTR of GBA mRNA to enhance glucocerebrosidase expression in Parkinson’s and Gaucher's disease (WO2023111337A1).
Master et al. 2016. A Novel Method for Gene-Specific Enhancement of Protein Translation by Targeting 5'UTRs of Selected Tumor Suppressors, 2016
See more: PATENTS
Software alowing for identification of cis-acting elements for modulating mRNA translation.
Software alowing for identification of cis-acting elements for modulating mRNA translation.
dGenhancer (Master A) is a software tool designed to predict translation-inhibiting cis-acting elements and to design eRNAs/dGoligos, which act as trans-acting factors that reduce Gibbs energy–dependent secondary structure formation. The project enabled the development of software capable of identifying cis-acting elements—potential target sites (see maxima peaks below) for dGoligos/eRNAs (synthetic trans-acting factors)—designed to enhance the translation of selected mRNA variants by targeting specific sequences in the 5'UTR or selected regulons (groups of RNAs) containing similar secondary structures. Principal Investigator and Software Engineer: Adam Master The software's capabilities were successfully validated and published in a collaborative study involving BioTe21 Genetic Laboratory, the Center of Postgraduate Medical Education (CMKP) in Warsaw, and Imperial College London (Master et al. 2016, supplementary data).
See more INVENTIONS
dGenhancer enabled the identification of a translation-inhibitory cis-acting element (green peak on the left) within the 5′ UTR of TRβ1. Binding of a trans-acting factor to this element triggered enhanced translation of the reporter protein.
The naturally occurring microRNA hsa-miR-211 was identified as a trans-acting factor capable of binding both the 3′ UTR and the 5′ UTR of TRβ1. Within the 5′ UTR, hsa-miR-211 overlaps with and covers the inhibitory cis-acting element (green peak) leading to enhancement of protein tranlsation. PMID: 27171412
Targeting G-quadruplexes
Targeting G-quadruplexes
Master A, Nauman A. Gene expression regulation by long naturally occurring antisense transcripts. Post. Biol. Kom. 2014;41(1):3-28. Review. link, PDF [pl] Machine translated by google PDF [en]
Master A, Nauman A. Genomic context and expression regulation of nuclear thyroid hormone receptors by long naturally occurring antisense transcripts. Post. Biol. Kom. 2014; 41(1):29-58. Review. link, PDF [pl] PDF [en]
Naturally occurring trans-acting factors
targeting cis-acting elements
Naturally occurring trans-acting factors
targeting cis-acting elements
Adam Master, Anna Wojcicka Alicja Nauman Gene-specific enhancement of protein synthesis by targeting 5’UTRs -a novel oligonucleotide-based strategy for translational control of selected tumor suppressors. 3rd International Conference and Expo on Drug Discovery & Designing. Volume 6, Issue 4(Suppl), p47, Drug Design Journal, ISSN: 2169-0138 DDO, October 02, 2017, Vienna, Austria.
Naturally occurring trans-acting factors
targeting cis-acting elements
Naturally occurring trans-acting factors
targeting cis-acting elements
Master A, Wojcicka A, Nauman A. The 5’UTR-dependent enhancement of protein translation efficiency triggered by self-transfecting 3’-aminoallyl-containing oligonucleotides (aa-dGoligos) targeting a pool of strongly folded transcript variants of the THRB suppressor gene. 1The Centre of Postgraduate Medical Education in Warsaw, Department of Biochemistry and Molecular Biology, Poland. 2Genomic Medicine, Depart. of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland. Molecular Therapy, Volume 22, Supplement 1, S38. May 2014 (Nature Publishing Group). The 17th Annual Meeting of the American Society of Gene & Cell Therapy, May 21-24, 2014 Washington, DC, USA. POSTER
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