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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.”

Remember that messenger-RNA-based Covid-19 vaccine you got? Just a few days later, the teeny molecular messengers contained in the shot were already gone.

Despite scientists’ best attempts to bolster mRNA and improve its stability, these molecules are ephemeral.

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That’s not necessarily a bad thing. A short, sharp burst of protein can be enough to rev up an immune response. And for gene therapies, the brief lifetime of mRNA is a major plus — you wouldn’t want DNA-cutting enzymes running rampant in your cells after they’ve already made a helpful genetic edit.

In some cases, however, a patient might need to produce high levels of a therapeutic protein for a prolonged period of time to benefit from a treatment. And reaching those levels with current mRNA technology isn’t always feasible. That’s because while repeatedly injecting high doses of mRNA into mice might look good in the lab, the benefits often show up only at doses so high that they wouldn’t be safe in people.

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“For the field of mRNA, one of the big white whales for a long time is protein drug replacement,” said Nathaniel Wang, CEO of Replicate Bioscience.

Wang’s company is among those devising a workaround for this problem: messenger RNA that makes more of itself once it is taken up by cells. This may sound improbable, but so-called self-replicating RNA works because the mRNA molecule doesn’t just code for a therapeutic protein. It also codes for proteins normally found in viruses which allow them to copy their RNA genomes once they’ve slipped inside a cell.

In effect, self-replicating mRNA comes with its own copying machine.

The result is the production of molecules that can last for up to around two months in the body, according to initial laboratory studies, suggesting that these therapies could achieve effects that would otherwise take roughly 1,000 times the dose of non-replicating RNAs. The potential benefits, Wang said, are twofold: Administering low doses could make these therapies safer, and they could allow researchers to divvy up a given batch of therapeutic mRNA among more patients who are in need.

But it’s a strategy that also comes with its own challenges, as a new STAT Report explains. Self-replicating mRNAs are longer than regular mRNAs because of the self-copying machinery they encode — they can stretch up to 16 kilobytes compared to a couple of kilobases for non-replicating mRNA. At that point, simply keeping the molecule together isn’t easy.

“The manufacturing challenge of having a product that has good integrity and good potency and purity” is potentially more of an issue for these larger RNAs, said Jeffrey Ulmer, who has been working in the field for 30 years and is a consultant and adviser to Replicate and several other mRNA companies.

Still, Replicate has managed to synthesize mRNA of up to 16 kilobases after tweaking its manufacturing process. The San Diego company, launched in February 2020, has raised about $53 million. It is now working on a treatment for patients with estrogen-receptor positive breast cancer who have developed resistance to hormone-targeted therapies, resulting in cancer cells metastasizing throughout the body. Another one of the company’s oncology treatments encodes immune cytokines and proteins meant to make tumors more responsive to immune attacks.

Replicate is also developing self-replicating mRNA to treat inflammatory and autoimmune disorders like arthritis and colitis, by encoding proteins that essentially soak up inflammatory cytokines. Wang said that the company aims to get at least one of these drugs into clinical trials in 2023.

Another San Diego biotech, Arcturus Therapeutics, is focused on a different use of this technology: vaccine boosters. The reason, explained Arcturus CEO Joseph Payne, is that a tiny bit of self-amplifying mRNA could go a long way toward reigniting the body’s immune responses by restimulating these cells with high levels of a viral protein.

It’s a strategy that Arcturus, a publicly traded biotech founded in 2013, is testing with a self-replicating Covid-19 vaccine that is currently in clinical trials. And in mid-August, Arcturus reported data indicating that clinical trial participants who’d received the company’s vaccine as a booster still had high levels of antibodies that could block Omicron variant BA.5 six months after getting the shot.

In the long run, Payne said, he thinks self-replicating mRNA could also allow researchers to develop mRNA therapies that aren’t feasible right now.Some of the proteins in your cells last several days, while others last less than an hour. And producing a protein that’s going to break down almost immediately isn’t much help unless you can keep churning out new copies. That’s why current mRNA therapies work best for longer-lasting proteins. But having a self-copying pool of mRNA could allow cells to continue to churn out proteins that are both ephemeral and important.

The technology is drawing financial interest. Arcturus recently struck a deal with Australian life science company CSL Seqirus licensing its self-amplifying technology for an upfront payment of $200 million and, potentially, $4.3 billion in future milestone payments.

“It’s still challenging, it’s still very early,” Payne said. But, he added, “We’re really excited about that part of our pipeline.”

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