Ancient Molecule, Modern Medicine: The Science, Strategy, & Stakeholders Behind tRNA Therapeutics

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

In May, I published “Raiders of the Lost Codon: Alltrna on Evolving ‘Ancient’ tRNA into Therapeutics,” with Alltrna CEO, Michelle Werner. As the title of this previous article should imply, my hour-long foray into the “ancient” molecule tRNA with Werner gave me Indiana Jones vibes that simply could not be ignored.

I’m thrilled to say that the treasure hunt continues here in this second installment. As I emphasized in my previous article, the work we must do to understand and communicate the biology behind our products and their mechanisms of action is akin to that of archaeologists bringing once-hidden artifacts out into the light for the benefit of society.

Of course, my conversation with Werner dug into the basics of how tRNA functions in vivo, as well as what tRNA can offer patient populations compared to that of other xRNA molecules and advanced therapies. However, as we all know well, “unearthing” our molecules’ potential poses numerous technical and business-related challenges for young biotech companies. Here, Werner and I continue our conversation, unpacking some of these internal and external challenges the company is navigating as it strives to bring tRNA to the commercial market.

Learning Our Molecules: What It Takes To Improve Upon Nature

As we explored in part 1, tRNA is an “ancient molecule” that has always played a critical role in protein translation. Of course, we can say most of our RNA modalities are “ancient” and leave it as a catchy marketing tagline. However, it’s clear following my conversation with Werner that that long history of tRNA lays the foundation for the modern work that Alltrna is doing to develop therapeutic tRNAs.

“Natural tRNAs are highly modified RNAs,” she explained. “So, we actually use endogenous tRNA modifications as inspiration for where to begin designing our molecules, and then we improve upon nature.”

Thanks to machine learning-guided sequence optimization and chemical modification — with siRNA chemical modifications being another source of inspiration, as well — the company’s lead candidate has successfully demonstrated protein restoration in preclinical animal models.

However, to get to this point, the company has had to dedicate its time and investment in machine learning and analytical development to understand what makes for a “good” tRNA molecule and, more importantly, what makes for an effective therapeutic tRNA. After all, as Werner acknowledged, the number of potential tRNA sequences and modifications dictating the molecules’ therapeutic performance is vast.

“The number of tRNA patterns possible could rival the number of atoms in the universe,” Werner said.   

As Werner went on to describe, there are several critical factors demanding optimization, starting with each tRNA’s “literacy,” if you will — or how well each construct can read through the premature termination codon. Likewise, learning how much tRNA needs to be delivered to each cell type and each molecule’s half-life are both essential measurements for determining a candidate’s dosing frequency.

Being one of the front runners developing a new modality can be just as alluring and exciting as being the first to make an archaeological discovery; however, as we also can imagine, it comes with its fair share of challenges. Though tRNA itself as a molecule was discovered decades ago, many of the questions we need to answer about how to turn it from a molecule into a medicine required tools and/or approaches that didn’t yet exist.

“How do you quantify tRNA?” Werner asked. “How do you characterize an engineered tRNA vs. an endogenous tRNA? Given that tRNA is one of the most abundant forms of RNA in each cell, we must be able to differentiate the engineered from the endogenous tRNAs to ensure we know how much of the therapeutic tRNA has been delivered into each cell.

Developing the tools to better understand therapeutic tRNA was one of the first priorities the company had to tackle — a challenge that, to some extent, was partially informed by the prior progress made in the mRNA and siRNA fields.

“I always say that Alltrna stands on the shoulders of the RNA giants who have come before us,” she added.

From Molecule To Meaning: Aligning tRNA Science With Patients’ Lives

But just as any good historian/archaeologist would emphasize, Werner reminds us that our “ancient” RNA molecules — like any historical object — becomes even more valuable when we understand the overarching context behind its creation/existence.

“We have amazing scientists and we’re doing amazing science at Alltrna,” Werner acknowledged. “Now we need to make sure that we’re doing science with a purpose. We’re not just doing science because it’s ‘cool,’ but we’re doing science because it has the potential to have a big impact on individuals who need novel therapies.”

Building the tools to understand the biological underpinnings and performance of our RNA products can only take us so far. We also must understand how our tRNA constructs function — or can best function — in relation to our patients’ needs. In turn, Werner has made engaging patient communities a core part of her leadership strategy at Alltrna from the earliest stages of development.

“It doesn’t matter what stage of a company you’re in — whether it’s discovery, preclinical, or clinical development,” she said. I believe that listening to the patient voice is paramount at every single step of the process.”

Werner or Chief Medical Officer Dr. Nerissa Kreher engage in the company’s discussions with patient advocacy groups as Alltrna sets out to design its first clinical trial. Of course, part of the dialogue between Alltrna and patient communities is centered around basic education about tRNA’s biological function and how that could translate into a therapeutic effect. Likewise, it’s equally important to ensure each patient gets the necessary genetic testing to understand the underlying mutation causing their disease because that mutation could dictate the treatment approach pursued. However, Werner also emphasized the importance of having patients’ input on the design of the company’s first trial. Though the regulators are a critical voice in establishing a trial’s endpoints, the data being collected must also be meaningful and relevant to each patient population.

“We listen to what their hopes and fears are; what their needs are; and what is important to them,” she added. “What are the qualitative things about their lives that they’re looking to serve with a new therapeutic innovation that comes to market for them? Is there a way for these engineered tRNAs to have a major impact on their quality of life?”

Be sure to check out Part 1 of this article series.

For the podcast aficionados amongst us, be sure to check out the Business of Biotech episode featuring Werner, my fabulous colleague Ben Comer, and yours truly.