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This story has been adapted from the STAT Report “The future of messenger RNA: Covid-19 vaccines are just the beginning.”

While billions of vaccine doses administered during the pandemic have generated reams of data about the safety and effectiveness of mRNA, they haven’t answered one of the field’s biggest questions: How do you send messenger RNA exactly where it needs to go in the body?

That’s because, for mRNA-based Covid-19 vaccines like those developed by Pfizer/BioNTech and Moderna, a shot in the arm did the trick. But in cases where mRNA is harnessed for other uses — such as targeting a specific set of tumor cells in a part of the body that’s hard to access — delivery won’t be so straightforward.

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Much of the field is convinced the answer lies with chemical tweaks to lipid nanoparticles, or LNPs, the blubbery balls used to encase mRNA and to shield these fragile molecules from destructive enzymes that would otherwise chop them up before they could be absorbed by cells. LNPs are already great at trafficking to the liver when administered systemically, as explained in a new STAT Report on mRNA, and companies are working on versions that could one day efficiently reach everywhere from bone marrow to the central nervous system.

But a few biotech startups are taking a completely different tack.

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“At the end of the day, I actually don’t care where the messenger RNA goes,” said Jacob Becraft, co-founder and CEO of Strand Therapeutics. “I care where it is expressing.”

His company, based in Cambridge, Mass., is one of a few that are focused on engineering mRNA so that it’s only used to produce protein in certain cells — a process known as translation — regardless of where the molecule ends up in the body. Strand’s strategy relies on so-called microRNAs, tiny molecules about 20 letters (or bases) long, that latch onto messenger RNA and cause it to be degraded. There are more than 2,000 microRNAs coded for in the human genome, and different tissues express them at different levels.

Strand, launched in 2017, is using data from public databases and from its own sequencing, combined with computational tools to identify microRNAs mainly made in certain tissues. And the biotech is harnessing that information to design mRNA sequences that will be degraded by microRNAs everywhere except in the tissue where researchers are trying to deliver a therapeutic protein.

The plan is to first test this strategy in an initial clinical trial in mid-2023 as a treatment for solid tumors like those in lung or kidney cancer. In the long run, Becraft said, Strand’s engineered mRNA could also be used for so-called in vivo cell therapies, which reach and reprogram specific cells, without removing them from a patient’s body.

Another Cambridge firm, Kernal Biologics, is also designing mRNA so that it is only translated in certain tissues. But the company is going about it in a different way, focusing on how messenger RNA attaches to ribosomes, the tiny protein-producing factories inside cells.

Kernal Biologics is harnessing machine learning to understand which proteins cancer ribosomes are more likely to churn out, and which they are less likely to produce. Much of that data comes from a technique called Ribo-seq, which uses enzymes to degrade free-floating RNA and sequence messenger RNA molecules that are attached to a ribosome (and thereby protected), giving researchers a snapshot of which proteins are being translated.

CEO and co-founder Yusuf Erkul said Kernal can design mRNAs that are selectively active in cancer cells but not in healthy cells. When the mRNA ends up in a healthy cell, he added, ribosomes either fail to start translation or stall during the assembly-like process of stringing amino acids into a new protein.

Kernal, founded in 2016, is focusing on cancers in which the tumor suppressor gene p53 isn’t working properly. Mutations in this gene are found in about half of all cancers and lead to unchecked cell growth.

The company is still testing its lead drug candidate in the lab, but Erkul said it hopes to begin a Phase 1 trial in the third quarter of 2023. That treatment, he said, will not be focused on a particular tumor type but on cancers where p53 is absent, with initial trials likely to focus on tumors close enough to the surface that a direct injection of mRNA is feasible, such as breast cancer, head and neck cancer, or thyroid cancer. The company hasn’t said what protein that mRNA therapy will encode, but it has said that the therapy will induce robust immune responses meant to shrink tumors.

“I’ve been watching this field very closely from before our conception,” said Erkul. “I haven’t seen anything like this in terms of onco-selectivity. This is as exciting as it gets.”

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