RNA editing has recently gained approval for clinical trials for two therapies aimed at treating genetic diseases, providing hope for safer treatments.

Manipulating RNA is gaining momentum and after years of basic research, three RNA editing therapies have either entered clinical trials or received approval for them, marking a significant milestone.

Advocates of RNA editing have long been touting its potential as a safer and more versatile alternative to genome-editing methods such as CRISPR. However, it poses significant technical challenges.

The launch of human trials signals the growing maturity and acceptance of the field, scientists say. “There’s a much greater understanding of RNA technology, and that’s been partially enhanced by the RNA vaccine and the COVID pandemic,” says Andrew Lever, a biologist at the University of Cambridge, UK. “RNA is now seen as a very important therapeutic molecule.”

The RNA molecule plays a crucial role in the process of protein synthesis. The genetic information stored in DNA is transcribed into messenger RNA (mRNA) before it is translated into proteins. RNA molecules are comprised of nucleotides, which contain one of four bases or letters.

RNA-editing methods aim to correct harmful mutations by modifying the sequence of RNA, allowing normal proteins to be produced. RNA editing can also enhance the production of beneficial proteins.

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RNA editing does not modify genes like CRISPR genome editing. Additionally, RNA editing does not bring about permanent changes since RNA molecules are transient. Therefore, the therapeutic effect of RNA editing could be temporary.

However, that transience could offer safety advantages. One risk of CRISPR therapies is off-target effects, or unintended changes outside the target genomic region, notes Joshua Rosenthal, a neurobiologist at the Marine Biological Laboratory in Woods Hole, Massachusetts. “An off-target effect in DNA is potentially quite dangerous. In RNA, it’s less so, because it’s going to turn over.”

One approach to RNA editing, known as single-base editing, uses an enzyme called ADAR that is already present in cells. This enzyme replaces adenine with inosine, thereby editing the RNA sequence. Wave Life Sciences, a company in Cambridge, Massachusetts, is exploring the use of single-base editing to treat alpha-1 antitrypsin deficiency (AATD), a genetic disorder that can harm the lungs and liver. This disease reduces production of AAT, a protein that protects the lungs from damage due to inhaling polluted air or other irritants.

Wave’s product involves a short chain of nucleotides that directs naturally occurring ADAR enzymes to change a specific letter in each mRNA molecule, correcting the mutation that affects AAT production. Wave’s president and CEO Paul Bolno explains that by using the cell’s own machinery to edit that single base, a normal protein can be made. In testing on mice, the drug edited around 50% of the target mRNA in liver cells, which is enough to produce therapeutic effects.

Another approach to RNA editing, called RNA exon editing, changes thousands of genetic letters in an RNA molecule simultaneously, rather than just one. RNA exon editing is useful for disorders caused by multiple mutations in a person’s genome, which are difficult to address with single-base changes. The technique targets pre-mRNA, which is transcribed from DNA and then processed to make mRNA. It includes both exons, which contain instructions for making proteins, and introns, which do not.

The introns are removed from the pre-mRNA via RNA splicing, and the exons are stitched together to form the final mRNA, which is then translated into protein. Companies like Ascidian Therapeutics in Boston, Massachusetts, leverage the RNA-splicing process to remove mutation-containing exons and replace them with healthy ones. Ascidian recently received FDA approval for a clinical trial of an exon editor to treat Stargardt disease, which causes vision loss. People with the disease have several mutations in a single gene, leading to the production of a defective protein that normally protects the retina.

Ascidian’s therapy involves an engineered DNA segment that is delivered into cells and produces normal RNA exons, replacing the mutated ones during the splicing process. This results in functional proteins. The DNA also produces RNA sequences that facilitate exon editing.

“With one molecule, [the therapy] is able to replace 22 exons at one time,” says biologist Robert Bell, head of research at Ascidian.

Cancer-quashing RNA

RNA-based therapies hold great potential beyond genetic diseases, as demonstrated by Rznomics, a biopharmaceutical company located in Seongnam, South Korea. In order to tackle hepatocellular carcinoma, the most prevalent type of liver cancer, Rznomics is currently testing an RNA editor. In September of 2022, the company initiated a clinical trial in South Korea, with plans to scale it up globally.

Rznomics’ strategy relies on mRNA splicing, but instead of using the cell’s own splicing machinery, the company employs a naturally occurring ribozyme, an RNA molecule that can trigger splicing in target areas of mRNA. Ribozymes were engineered by researchers to cut open mRNAs in tumor cells and inject a deadly cargo: an RNA sequence that translates to a protein, producing a toxin that induces cell death. Once neighboring cancer cells come into contact with these cells, the toxin spreads, promoting cell death. This therapeutic molecule replaces an RNA sequence that is linked to tumor growth.

The use of the splicing approach against more than one disease is very exciting, says Lever, who is also the chief medical officer of Spliceor in Cambridge, UK, a firm that is working on RNA-splicing therapies. “It opens up a whole new range of possibilities of treatment for things which otherwise can’t be treated.”

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