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Internal Ribosome Entry Sites of ESR1 and SARS-CoV-2 as a Platform for Gene Expression and Therapeutic Applications

Shorter IRES sequences to enhance mRNA vaccines, gene therapy, gene editing, cell-based therapies, and recombinant protein production.

Therapeutics

Project Overview

Internal ribosome entry sites (IRESs) are endogenous RNA sequences that can induce mRNA translation through the direct recruitment of ribosomes to specific RNA locations.
Current IRES technologies are hampered by large nucleotide lengths and low activity, restricting their utility in applications like mRNA vaccines and gene therapy. The novel IRES sequences for the estrogen receptor (protein: ER-alpha; gene: ESR1) and SARS-CoV-2 offer a solution.
Scientists at Dana-Farber designed and developed IRES sequences from ESR1 and SARS-CoV-2 that are significantly shorter and more active than traditional IRESs.
Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new therapeutics or vaccines.

Technology

Internal ribosome entry sites (IRESs) are endogenous RNA sequences that can induce mRNA translation through the direct recruitment of ribosomes to specific RNA locations, thereby addressing significant limitations in mRNA translation, which traditionally relies on chemical modification of the 5’ cap structure.

IRESs are important for a variety of reasons, including their ability to induce protein synthesis from endogenous mRNA via a cap-independent mechanism and the use of IRES sequences as tools to induce protein synthesis in various gene expression systems.

Current IRES technologies are hampered by large nucleotide lengths and low activity, restricting their utility in applications like mRNA vaccines and gene therapy. The novel IRES sequences for the estrogen receptor (protein: ER-alpha; gene: ESR1) and SARS-CoV-2 offer a solution by providing highly active and compact alternatives, facilitating cap-independent translation and expanding the potential of gene expression systems.

Dr. William Hahn and his lab at the Dana-Farber designed and developed IRES sequences from ESR1 and SARS-CoV-2 that are significantly shorter and more active than traditional IRESs. The minimal ESR1 IRES is approximately 20 nucleotides, and the SARS-CoV-2 IRES is approximately 100 nucleotides, compared to the 500+ nucleotides typical of other IRESs, such as the encephalomyocarditis virus (EMCV) IRES.

The reduced nucleotide length of these IRESs allows for their integration into size-constrained systems, such as viral vectors and circular RNAs, without compromising efficiency. Additionally, these IRES sequences exhibit at least 3-fold higher activity than EMCV, making them highly efficient for driving protein synthesis and facilitating more robust protein expression. This is crucial for applications requiring high protein yields, such as recombinant protein production and mRNA vaccines. The ability to modify these IRESs to either enhance or ablate their activity further provides versatility for various applications, from increasing protein production in therapeutic contexts to suppressing unwanted protein expression in disease models.

The novel IRES sequences for ESR1 and SARS-CoV-2 are ideal for a wide range of applications, from therapeutic interventions in breast cancer and COVID-19 to improving the efficiency of gene expression systems.

Team Members: William Hahn, MD, PhD, David Mayhew, MD, PhD

Applications

mRNA Vaccines: Streamlining production by eliminating the need for 5’ cap modifications.
Gene Therapy: Enhancing expression of therapeutic genes in viral vectors.
Gene Editing: Improving delivery and expression of CRISPR components.
Cell-Based Therapies: Boosting protein expression in CAR-T and other programmable cell therapies.
Recombinant Protein Production: Increasing yields in industrial and research settings.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new therapeutics or vaccines.

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