This story was adapted from the STAT report “The Future of Messenger RNA: Covid-19 Vaccines Are Just the Beginning”.
OWhile billions of doses of vaccine administered during the pandemic have generated reams of mRNA safety and efficacy data, they have not answered one of the field’s biggest questions: how to send messenger RNA exactly where it needs to go in the body?
Indeed, 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 the mRNA is being harnessed for other purposes, such as targeting a specific set of tumor cells in a hard-to-reach part of the body, delivery won’t be so straightforward.
Much of the field is convinced that the answer lies in chemical tweaks to lipid nanoparticles, or LNPs, the balls of fat used to envelop mRNA and to shield these fragile molecules from destructive enzymes that would otherwise chop them up before they go. can be taken up by the cells. LNPs are already excellent at trafficking to the liver when administered systemically, as explained in a new mRNA STAT report, and companies are working on versions that could one day effectively reach everywhere from the bone marrow bone to the central nervous system.
But a few biotech startups are taking a completely different approach.
“At the end of the day, I don’t care where the messenger RNA goes,” said Jacob Becraft, co-founder and CEO of Strand Therapeutics. “I care where he expresses himself.”
His company, based in Cambridge, Mass., is one of the few to focus on engineering mRNA so that it is only used to produce proteins in certain cells – a process known as translation – wherever the molecule ends up in the body. Strand’s strategy relies on so-called microRNAs, tiny molecules about 20 letters (or bases) long, which attach to messenger RNA and cause it to break down. There are over 2000 microRNAs encoded in the human genome and different tissues express them at different levels.
Strand, launched in 2017, uses data from public databases and its own sequencing, combined with computational tools to identify microRNAs primarily made in certain tissues. And biotechnology uses this information to design mRNA sequences that will be degraded by microRNAs everywhere except into the tissue where researchers are trying to deliver a therapeutic protein.
The plan is to first test this strategy in a first clinical trial in mid-2023 as a treatment for solid tumors like lung or kidney cancer. In the long term, Becraft said, Strand-modified 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 company, Kernal Biologics, also designs mRNA to be translated only 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 using machine learning to understand which proteins cancer ribosomes are more likely to produce and which they are less likely to produce. Much of this data comes from a technique called Ribo-seq, which uses enzymes to degrade floating RNA and sequence messenger RNA molecules that are attached to a ribosome (and thus protected), giving researchers a overview of proteins being translated.
CEO and co-founder Yusuf Erkul said Kernal can engineer mRNAs that are selectively active in cancer cells but not in healthy cells. When the mRNA ends up in a healthy cell, he added, the ribosomes either fail to start translation or stall during the process of assembling amino acids into a new protein.
Kernal, founded in 2016, focuses on cancers in which the p53 tumor suppressor gene is not working properly. Mutations in this gene are found in about half of all cancers and lead to uncontrolled 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. This treatment, he said, will not be focused on one type of tumor particular but on cancers where p53 is absent, with early trials likely to focus on tumors close enough to the surface for direct injection of mRNA to be feasible, such as breast cancer, head cancer and neck or thyroid cancer. The company did not specify which protein would encode the mRNA therapy, but it said the therapy would induce robust immune responses aimed at shrinking tumors.
“I’ve been watching this area very closely since before our conception,” Erkul said. “I haven’t seen anything like it in terms of onco-selectivity. It’s as exciting as it gets.