The Epitranscriptome Heads Toward Clinical Necessity

A deep understanding of epitranscriptomics—RNA modifications—is the missing layer in the quest for more broadly effective precision medicines. That’s the view of Gudrun Stengel, PhD, CEO of Alida Biosciences, and the foundational belief that drives her company to build sequencing tools and scientifically relevant models linking RNA modifications to phenotype.

Today, despite the astounding breakthroughs of the past quarter-century, positive responses to advanced therapies such as checkpoint inhibitors and cell and gene therapies are still limited to a relatively small subset of patients. To improve efficacy and understand patient response, Stengel says, “We need to consider all layers of epigenetic regulation to better understand gene regulation and build better models of biology, especially right now, with AI enabling the integration of huge amounts of data.”

Despite the increasing influx of information, “We still have gaps in our understanding of how information flows from DNA to proteins and ultimately phenotype,” Stengel says. In a multiomics environment, RNA modifications—which she calls “an essential layer of that multiomic stack”—have received relatively little attention because they are considered particularly hard to measure accurately.

To help resolve that issue, AlidaBio is focusing on three of the most important RNA modifications as a way to create better and more useful epitranscriptomics models to improve scientists’ understanding of the many layers of epigenetic regulation.

Why epitranscriptomics

“Epitranscriptomics are a readout of the cell state,” Stengel says. “Single-cell transcriptomics and spatial transcriptomics have shown a huge amount of heterogeneity—similar cell types are characterized by different RNA expression patterns that define what a cell is doing at a given time.” As an example of the timescales of response, she says, “To reset DNA methylation can take up to two weeks. To reset an RNA expression pattern can take a day, and RNA modifications can change RNA expression within a few hours.” Understanding those patterns and their time to action can significantly affect a cell’s response to therapeutics.

“RNA modifications don’t change the genetic code, but they change what RNA does,” Stengel emphasizes. “N6-methyladenosine (m6A), the most important mRNA modification, can quickly mark RNA transcripts associated with a previous cell state for degradation and, at the same time, promote the translation of genes that are associated with the future cell state. It is also involved in alternative splicing regulation, which creates more protein diversity.”

Epitranscriptomics method development has gained significant momentum in recent years. Current nanopore-based direct RNA sequencing can detect a subset of modifications in native, long RNA molecules. However, the approach currently requires relatively large quantities of high-quality full-length RNA.

Short-read, one-pot detection

Alida Biosciences expanded the industry’s capabilities in 2025 by launching its EpiPlex platform. It was the first commercial solution to analyze sparse and highly-degraded RNA often found in clinical samples and provide simultaneous, one-pot detection, localization, and quantification of three of the best-studied and most frequently occurring mRNA modifications: N6-methyladenosine (m6A), inosine, and pseudouridine, along with gene expression. The company offers kits, analysis software, and services.

“To develop clinical and translational applications, you need to look at clinical samples (fresh-frozen or formalin-fixed paraffin-embedded tissues, and liquid biopsies, for example) that are present at low quantities or that may be highly degraded,” she explains.

The long list of potential applications includes patient stratification for specific therapies and response monitoring, as well as therapeutic development of cancer drugs and measuring immune cell fitness. “m6A, the most common modification, plays a huge role in cell differentiation and cell fate,” Stengel says.

Entrepreneurial leanings

Stengel formed the company five years ago, leaving a safe corporate position on the belief that she could create a company that would fill a key knowledge gap.

“I had spent a significant number of years in large companies—including Illumina—developing genomics technologies,” she says. Researchers at such companies, however, tend to be involved in either the inception or the development of a product. “I wanted to see things through from the beginning to the end. I thought a smaller company would be the ideal environment to do exactly that. I resigned my job and started putting the pieces together.

“When I started the company, many [in the industry] had never heard of epitranscriptomics,” she says. Nonetheless, she secured venture capital funding within six months and built a small, core team.

Those early days found her in the lab, working with just a few scientists. “Getting the first, preliminary data was so exhilarating!” she recalls. “It’s a good day when everything works in the lab.”

Epitranscriptomics is emerging from a niche discipline, so now most conference attendees, “regardless of the conference,” Stengel adds, are aware of the field. Although, she admits, “not everybody knows why they are important. Yet, that’s a huge step forward.”

Commercial vision

As scientists increasingly recognize the role RNA modifications play in therapeutic development and outcomes, she can focus on scaling the company and its commercial capabilities. “We started out very R&D heavy,” and now are beginning to earn revenue to fund further innovations. Potential clients include multiomics companies, research hospitals, and “to some extent, diagnostics,” she says.

Currently, AlidaBio is working with the oncology company STORM Therapeutics to understand the mechanism of action and to stratify patients for a Phase II drug that acts on methyltransferase-like 3 (Mettl3), the m6A writer enzyme. This is one of a few areas in which RNA modification can make breakthroughs in patient treatment and stratification, she says. “We’re also very interested in predicting response to PD-L1 inhibitors.”

For AlidaBio, bioinformatics is an area of continual focus, along with making analysis output more interactive. “We also are applying machine learning models to integrate the amount of information between RNA modifications and gene expression, so there will be significant updates to the EpiScout^® analysis software,” Stengel says. Other plans remain confidential.

For both the company and the industry, “I think the next inflection point is when epitranscriptomics becomes part of mainstream multiomics,” Stengel says. When that happens, researchers will consider RNA expression data incomplete without information about RNA modification.

Therefore, eventually, “RNA modifications will become another standard layer that’s integrated into AI models of biology,” she continues. “The real test will be demonstrating that this layer improves patient stratification, predicts treatment response, or identifies new therapeutic opportunities. Once that happens, I think the field will move from being scientifically interesting to clinically indispensable.”

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