mRNA expression control

Beyond Peak Expression: Rethinking Control in mRNA Therapeutics

by Serena Marletta
2 min read
Jun 11, 2025 5:11:18 PM
In a nutshell

From maximum to meaningful

mRNA therapies are evolving: it’s no longer about producing more protein, but producing the right amount in the right place. This post outlines how expression control can support safer, more precise, and tissue-specific mRNA design.

When Expression Becomes a Liability

In the early days of mRNA therapeutics, maximizing protein production was a natural goal—particularly for prophylactic vaccines, where antigen load drives immune response [1]. That approach may warrant reconsideration as applications diversify.

A preclinical study by Sedic et al. evaluated the delivery of mRNA encoding human erythropoietin (hEPO) via lipid nanoparticles (LNPs) in rats and non-human primates. Despite successful delivery and robust expression, the study reported systemic toxicity resulting from excessive protein levels—approximately 100-fold higher than therapeutic thresholds. This overexpression led to adverse outcomes such as extramedullary hematopoiesis, elevated liver enzymes, tissue damage, and immune activation [2]. In other words, even with effective targeting and functional protein, too much expression proved harmful.

This highlights a broader point:

Controlling expression levels is essential to ensure safety and efficacy, even when delivery is accurate.

Despite its impact on safety, efficacy, and specificity, expression control is rarely treated as a standalone design parameter. It is often addressed indirectly—through dosing or formulation tweaks—rather than built into the mRNA sequence itself.

The Case for Expression Modulation

While delivery remains the most urgent challenge in mRNA therapeutics—rightfully drawing much of the field’s attention—it is only part of the story. Once the mRNA reaches its destination, what matters next is how protein levels are distributed and regulated within and across tissues.

A study by Shenoy et al. introduced a tumor-restricted IL-12 mRNA circuit (STX-003) designed to minimize off-target expression in immune tissues like the spleen. The circuit sharply reduced IL-12 levels in the spleen, reducing systemic toxicity while maintaining therapeutic effects in tumors [3]. This demonstrates how post-delivery expression control—especially suppression in off-target tissues—can expand the therapeutic window.

At Officinae Bio, we take a complementary approach. Rather than programming regulatory logic into genetic circuits, we optimize the mRNA sequence itself to enable differential expression across tissues. Our UTR-tuned constructs are designed to enhance specificity and modulate expression levels—providing a layer of control that works in synergy with  delivery systems to achieve safer and more effective outcomes.

stylized_mrna_rotating

Designing Expression to Fit Biology

We focus on expression fidelity—tailoring the output to meet therapeutic goals without overwhelming tissues. Through rational design of untranslated regions and codon usage, we aim to:

  • Boost translation efficiency where it matters

  • Limit protein load in off-target sites

  • Reduce required dosing through more precise control

When delivery systems bring mRNA to the right location, sequence design ensures that the cellular response is appropriate.

From Message to Mechanism

The push for maximal output made sense in urgent vaccine development. Today, mRNA must meet the needs of varied indications, from oncology to rare diseases. What’s needed isn't simply more—it's better-calibrated expression.

At Officinae Bio, we see mRNA not merely as a vehicle—but as a programmable message. How that message is written determines what the cell does with it. Rational sequence design aligns the message with therapeutic intent.

References

  1. Sahin, U., Muik, A., Derhovanessian, E. et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature 586, 594–599 (2020). https://doi.org/10.1038/s41586-020-2814-7

  2. Sedic M, Senn JJ, Lynn A, et al. Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey. Veterinary Pathology. 2017; 55(2): 341-354. doi:10.1177/0300985817738095

  3. Shenoy GN, Tseng WA, Clinton EA, et al
    1328 STX-003: utilizing programmable genetic circuits for tumor-specific IL-12 expression and reduced toxicity with systemically delivered mRNA. Journal for ImmunoTherapy of Cancer 2024; 12: doi: 10.1136/jitc-2024-SITC2024.1328

     
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