Jake Becraft: Origins of Strand and the Future of RNA Therapy (Nucleate Insights #2)

Background

Jacob Becraft, CEO of Strand Therapeutics

Insights’ guest for this session was Jake Becraft, synthetic biologist, entrepreneur, CEO and co-founder of Strand Therapeutics, a company at the forefront of mRNA therapeutics and synthetic biology. Together with colleagues at MIT’s renowned Synthetic Biology Center, Jake led the development of the world’s first synthetic biology programming language for mRNA. In 2018, he and his colleagues published Small-molecule-based regulation of RNA-delivered circuits in mammalian cells in Nature Chemical Biology, forming the basis for Strand Therapeutics.

Jacob Becraft, Ph.D., CEO, Co-founder at Strand Therapeutics

Scientific Context

The idea of “mRNA therapeutics” catapulted itself into the public conversation in 2020. However, mRNA as a therapeutic had been a subject of great interest for scientists and clinicians long before its introduction as the molecule behind the COVID-19 vaccines. Messenger RNA (mRNA) is a cell’s solution to transcribing the code of DNA into an intelligible “message” which ribosomes can then “read” to create functional proteins. DNA resides within the protective shell of the nucleus, whereas mRNA exists in the cytoplasm of the cell where it is translated into protein then degraded thereafter. Both DNA and mRNA can be generated and delivered to patients therapeutically to produce proteins needed by the patient. The functional and regional distinctions between DNA and mRNA are central to how we think of these two molecules in the context of clinical utility. The major advantages of mRNA-based clinical applications are two-fold:

  1. mRNA is restricted in location and activity to the cell’s cytoplasm. Unlike DNA-based therapies which require specific engineering to cross the complex nuclear membrane, mRNA has only one barrier to cellular entry — the cellular membrane itself. Additionally, there is virtually no risk of genomic integration as mRNA does not enter the nucleus or get retro-transcribed to DNA.
  1. Control — The safety and efficacy of mRNA-based therapeutics requires a precise control over the strength and timing of protein expression to avoid the over-, under-, or mis-timed- expression of a protein.
  2. Specificity — It is critically important that whatever mechanisms are used to control mRNA expression level and timing are specific to the therapeutically introduced mRNA and will not affect any other mRNA in the recipient’s body.
  3. Immunogenicity — Introducing novel mRNA can trigger an immunogenic response which poses a considerable safety risk.

Key Insights

1. Minding the Gap

The Gap: Early in Strand’s development, Jake and his team were following the immuno-oncology (I-O) space closely and thinking about how mRNA fits into the picture. A major approach to I-O is based on the delivery of specific cytokine cocktails to solid-tumors in the hopes of creating an appropriate immune response to clear the tumor. Moderna, a pioneer of mRNA-based approaches to protein delivery, was running up against challenges in duration and specificity.

2. Making the Point

Version 1: Jake is not shy to admit that the first version of Strand’s investor pitch deck was…rough. Jake describes how easy it is to forget that while you are embedded in your world and driven by an intrinsic knowledge and sense of the vision you have for your technology, investors are seeing this for the first time and need to be effectively brought into your world. Strand’s early pitch leaned heavily on data and scientific/mechanistic theory.

3. Engineering the Solution

Where to Take Risk: In defining a clinical indication and business strategy, Strand leaned on a central philosophy of engineering-led problem solving. They understood that their strength is in the programmable mRNA platform. So instead of innovating on a novel biological target, they aimed for a target that was previously robustly validated. This allowed the team to leverage their strengths and focus on developing the platform tools rather than validating new biology.

4. Leading the Company

Chief “Liaison” Officer: As Jake stepped into the CEO role, he shifted his frame of mind from a “scientist” phenotype to a “liaison” phenotype. Jake now sees his role as, “a liaison between capital market and capital expenditure.” He projects research ideas to the capital market, gathers feedback, then carefully uses the feedback to inform the team’s direction. Jake sees this process of navigating, negotiating, and communicating as a critical set of skills that any successful CEO should be constantly growing into.

5. Building the Future

Manufacturing: One of the challenges facing mRNA manufacturing is the length of the mRNA strand. The manufacturing process can result in mRNA products which are not the full-length desired product. The longer the desired strand, the harder to produce a high percentage of full-length products. Currently, Strand is relying on CDMOs to manufacture GMP-grade mRNA but they eventually plan to bring manufacturing in-house. Strand sees the manufacturing process itself as another engineering problem which they are poised to resolve and are incentivized to tailor to their particular mRNA platform.

Learn more

Thank you to all who participated in this vibrant discussion! To dig deeper into the details, check out the full recording of this Insights session.

Author

Ackowledgements

About Nucleate
Nucleate is a nonprofit organization dedicated to empowering the next generation of biotech leaders, with chapters spanning 10 regions and participation from over 70 academic institutions. Nucleate identifies future biotech entrepreneurs, removes barriers, and helps founders concentrate on building transformational technologies.

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