The Secret to Your Therapeutic Success: Comprehensive mRNA Design

TLDR: When developing mRNA therapeutics, the complex relationship between sequence design and therapeutic performance can't be overlooked. At Terrain, we've built our services around a fundamental principle: to achieve optimal results, you have to design for the whole mRNA molecule. 

Our design approach combines deep biological expertise with AI/ML tools that assess multiple parameters simultaneously. We optimize all aspects of your mRNA to achieve your therapeutic goals.

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Understanding Sequence Space and Therapeutic Space

At Terrain, we think about mRNA design through two conceptual frameworks:

Sequence space refers to the actual nucleotide composition of the mRNA molecule—the specific arrangement of As, Gs, Cs, and Us that make up your therapeutic. This is where our design expertise comes into play, as we make targeted modifications to optimize performance and manufacturability.

Therapeutic space represents the outcomes that matter most to drug developers: expression levels, stability, immunogenicity, and specificity. These therapeutic attributes directly impact your drug's efficacy, safety, and manufacturability.

Our expertise lies in understanding the complex relationship between these two spaces—how changes in sequence space translate to improvements in therapeutic space.

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The Comprehensive Design Review: Where Partnership Begins

Our partner-centric approach starts with a Comprehensive Design Review. This collaborative process is the foundation of our relationship with partners and includes:

• Deep discussions about your disease biology and therapeutic goals
• Analysis of your current sequence performance and limitations
• Understanding of your target tissues and cell types
• Review of your development timeline and manufacturing needs
• Identification of specific challenges you're facing

This intensive knowledge-sharing ensures we fully understand your context before making any design recommendations. Rather than treating your mRNA like any other sequence, we see our Design Review as a critical component of your therapeutic’s success.

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Understanding the mRNA Architecture

The infographic above illustrates the critical connection between the structural components of mRNA and the therapeutic attributes drug developers care about most.

The mRNA molecule isn't just a linear string of nucleotides—it's a dynamic, three-dimensional chemical structure with distinct functional regions:

• 5' UTR: Influences expression and plays a critical role in translation initiation
• Coding Sequence (ORF): Determines the amino acid sequence of the protein and thus its expression, stability, and immunogenicity 
• 3' UTR: Affects stability and can be engineered for cell-type specificity‍
• Poly(A) Tail: Crucial for expression and stability, with dire consequences for truncations

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The Multi-Dimensional Challenge of mRNA Design

The lines in our graphic show what makes mRNA design particularly challenging: each region doesn't operate in isolation. The intricate relationships between sequence space and effect space require a holistic design approach:

1. Expression: Influenced by the 5' UTR, coding sequence, and poly(A) tail
2. Stability: Affected by coding sequence choices, 3' UTR elements, and poly(A) tail length
3. Immunogenicity: Dictated by the coding sequence
4. Specificity: Can be engineered through 3' UTR elements

This complexity means that optimizing for one attribute (like expression) without considering its effects on other attributes (like stability) can lead to unexpected consequences.

And, underpinning all of this is manufacturability: we also have to ensure that your mRNA sequence can be reliably produced at scale. A classic multi-objective optimization problem!

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Terrain’s Design Approach

Rather than focusing on individual components separately, we design with the entire molecule in mind.

Our design approach combines deep biological expertise with AI/ML tools that assess multiple parameters simultaneously. We don't just focus on one aspect of your mRNA; we look at how all the components work together to achieve your therapeutic goals.

By designing for the whole mRNA and bridging the gap between sequence space and effect space, we help ensure that your therapeutic performs as intended—from expression to stability, from immunogenicity to specificity, and ultimately, to successful clinical outcomes.

Whether you're early in discovery or preparing for clinical trials, our Comprehensive Design Review and holistic approach to mRNA design can help you navigate the complex challenges of therapeutic development more effectively.

Wondering if your sequence is the problem? Chat with our team and let's find out.