A sweeping form of search-and-replace editing has come for mRNA

For several years now, biotechs have enthused over DNA-altering technologies that allow the editing of any genetic sequence by swapping out defective or unwanted code for a new one. Now, a handful of startups and academic groups are working on a similar approach for short-lived mRNA molecules.

The goal is to combine the benefits of large-block edits with the more versatile, less permanent and potentially safer target of mRNA. While the new technologies go by many names, scientists familiar with the work told Endpoints News that the techniques were inspired by the conceptually analogous prime editing. Some call it RNA writing.

“Think of the genome as a book,” Jacob Borrajo, co-founder and CEO of the RNA writing startup Amber Bio, told Endpoints. While other gene editing technologies change individual letters, or maybe a few words, he said, “We want to change whole pages at a time.”

RNA writing is the latest in a succession of technologies from a decadelong, CRISPR-inspired gold rush, with each new advance claiming to overcome the problems of predecessors and open new doors for therapies. These latest tools may prove useful in treating conditions that can be caused by numerous typos in a gene that’s too big to replace wholesale, using existing gene therapy methods.

Last week, Ascidian Therapeutics — the emerging field’s frontrunner — announced plans to put that idea to the test in a clinical study of a therapy that rewrites roughly two-thirds of the genetic typos responsible for an inherited form of vision loss. Within days, scientists from UC Berkeley, MIT and Duke University posted studies on the preprint server bioRxiv disclosing their own RNA writing methods, and potential applications in numerous brain diseases including ALS, autism, and Huntington’s disease.

“RNA writing kind of evokes the concept that you can do anything in RNA,” Omar Abudayyeh, a researcher at MIT and co-author of one of the RNA writing preprints, told Endpoints. “You can really make any change you want.”

From single letters to mass swaps

The new tools work by hijacking RNA splicing, a natural process that cells use to slice and dice rough drafts of the messenger molecules into finalized blueprints for making proteins.

For most organisms, including humans, RNA splicing occurs within a single molecule, cutting out stretches of genetic padding known as introns, and stitching the protein-coding exons back together. But some creatures, including sea squirts and worm-like parasites called trypanosomes, can mix and match exons from different strands.

Scientists first tried to replicate that genetic shuffle, a process called RNA trans-splicing, in human cells more than two decades ago, but early efforts floundered. The new tools rely on CRISPR enzymes or synthetic RNA to manipulate splicing. And they’re debuting at a time when interest in RNA has never been greater.

“RNA is front and center, in a really kind of generational way,” Patrick Hsu, a researcher at the Arc Institute and UC Berkeley, told Endpoints. The development of mRNA therapies by companies like Moderna helped thrust the messenger molecules into the limelight, but Hsu thinks that RNA writing represents the next level of sophistication.

“We have the potential to universally and programmably correct, insert, delete, or swap out any sequence of interest,” Hsu added.

Researchers hope the technique may lead to the creation of one-size-fits-most therapies for genetic diseases caused by many mutations. And since the technique doesn’t tamper with DNA, it could also lead to some creative genetic tinkering, such as reshaping proteins to temporarily dull pain or dampen inflammation.

The transient effects of RNA writing are also a major selling point for another form of RNA editing — this one analogous to CRISPR base editing — that harnesses a human enzyme called ADAR to change a single letter in the molecules. That technology entered clinical trials for the first time late last year.

“The reversibility cuts in a lot of different ways,” MIT researcher Jonathan Gootenberg told Endpoints. “There are many drugs and indications where you want to have a temporary effect and not a permanent effect.”

Into the clinic

Ascidian, which has raised $90 million since its founding in 2020, expects to begin the first RNA editing clinical trial in the US this spring. It has divulged little about the specifics of its technology — which it calls exon editing — beyond a few posters and presentations at scientific conferences. But the startup’s head of research, Robert Bell, told Endpoints the therapy is a “designer RNA” that simultaneously targets the genetic code of interest, recruits the cell’s splicing machinery, and encodes new RNA that gets swapped in.

Other groups developing RNA writing tools apply variations on that theme, often with the help of CRISPR enzymes adept at targeting RNA instead of DNA.

Amber Bio emerged from stealth in August with a $26 million seed round, and describes its technology as “multi-kilobase RNA editing.” A preprint that the startup’s founders published two weeks after the company launched revealed that it uses CRISPR enzymes called Cas13 and RNA molecules to coax cells into what it calls “splice editing.”

Two other preprints posted last week — both written by protégés of CRISPR pioneer Feng Zhang — revealed additional ways to trigger trans-splicing. And petri dish experiments showed that the techniques could correct genetic flaws linked to several brain diseases.

One study from Hsu’s lab described a method dubbed RESPLICE, which uses Cas13 to spur trans-splicing and a second CRISPR enzyme called Cas7-11 to inhibit normal splicing. Another study, led by Gootenberg and Abudayyeh from MIT, presented versions of a method they called PRECISE, one based on Cas7-11 and another based on a synthetic RNA molecule.

And on Thursday, researchers led by Duke gene therapy scientist Aravind Asokan published a preprint using a Cas13-based method for RNA writing.

“RNA is maybe like the magic layer of the central dogma of molecular biology,” Hsu said. “There’s just tremendous potential for manipulating things at the RNA level that we’re going to kind of see over the coming years.”

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