The momentum behind RNA editing is unmistakable. Following years of foundational research exploring the intricacies of manipulating this intricate molecule, at least three therapies leveraging RNA editing have either commenced clinical trials or obtained approval to do so. These pioneering treatments mark a significant milestone in the field.
Advocates of RNA editing have long contended that it represents a potentially safer and more adaptable alternative to genome-editing methodologies like CRISPR. Nevertheless, it presents formidable technical challenges.
The initiation of human trials underscores the growing maturity and acceptance of RNA editing, according to scientists. Andrew Lever, a biologist at the University of Cambridge, UK, emphasizes that the broader understanding of RNA technology, partly catalyzed by the RNA vaccine and the COVID-19 pandemic, has elevated RNA’s status as a pivotal therapeutic agent.
RNA editing: A transient yet promising therapeutic approach
RNA plays a pivotal role in the process of protein synthesis. Initially, the genetic information stored in DNA undergoes transcription, resulting in the formation of messenger RNA (mRNA), which is subsequently translated into proteins. RNA molecules are constructed from nucleotides, each containing one of four bases, or letters.
RNA-editing methodologies strive to counteract deleterious mutations by altering the RNA sequence, thereby facilitating the synthesis of normal proteins. Furthermore, RNA editing has the potential to augment the production of advantageous proteins.
In contrast to CRISPR genome editing, RNA editing does not modify genes, nor does it induce permanent alterations, as RNA molecules are transient. Consequently, the therapeutic effects of RNA editing may have a shorter duration.
However, this transient nature could offer safety benefits. Joshua Rosenthal, a neurobiologist at the Marine Biological Laboratory in Woods Hole, Massachusetts, highlights the risk of off-target effects associated with CRISPR therapies. Off-target effects refer to unintended alterations occurring outside the intended genomic locus. Rosenthal underscores that while off-target effects in DNA can pose significant risks, those in RNA are comparatively less hazardous due to the turnover nature of RNA molecules.
Harnessing ADAR enzymes for RNA editing in genetic disorders
Employing a common RNA-editing strategy known as single-base editing, Wave Life Sciences based in Cambridge, Massachusetts, taps into the enzyme adenosine deaminase acting on RNA (ADAR) found within cells. This enzyme facilitates the exchange of adenine for inosine in RNA sequences.
Wave is investigating single-base editing as a potential remedy for alpha-1 antitrypsin deficiency (AATD), a genetic ailment that can impair lung and liver function. AATD hampers the production of AAT, a crucial protein synthesized in liver cells to safeguard the lungs against harm from inhaling pollutants and irritants.
The company’s product involves a short nucleotide chain guiding ADAR enzymes, naturally present in cells, to rectify a specific letter in each mRNA molecule, thereby correcting the mutation affecting AAT production. According to Paul Bolno, Wave’s president and chief executive, “By using the cell’s endogenous machinery to edit that single base, you now make a normal protein. And we’ve shown that the normal protein can be expressed at high levels,”
In preclinical studies involving mice, the medication successfully edited approximately 50% of the targeted mRNA in liver cells, a level deemed therapeutically effective by Bolno. Wave initiated clinical trials for the drug in December, conducted in the United Kingdom and Australia, to assess its safety profile and other attributes.
The promise of RNA exon editing
An alternative methodology, known as RNA exon editing, offers a distinct approach by simultaneously altering thousands of genetic letters within an RNA molecule, rather than targeting individual nucleotides. Described as akin to editing an entire paragraph rather than fixing a single typo, this approach proves particularly beneficial for addressing disorders stemming from multiple mutations across an individual’s genome—challenges that are difficult to tackle through single-base modifications.
This technique focuses on pre-mRNA, which is transcribed from DNA and undergoes processing to generate mRNA. Pre-mRNA comprises both exons, containing protein-coding instructions, and introns devoid of such directives. Through RNA splicing, introns are excised from pre-mRNA, and exons are spliced together to form mature mRNA, which subsequently directs protein synthesis.
Enterprises like Ascidian Therapeutics in Boston, Massachusetts, harness the RNA-splicing mechanism to excise mutation-laden exons and substitute them with healthy counterparts. Recently, Ascidian obtained approval from the US Food and Drug Administration for a clinical trial involving an exon editor designed to address Stargardt disease, a condition characterized by progressive vision loss resulting from mutations in a single gene.
Ascidian’s therapeutic approach relies on an engineered DNA segment, administered into cells to generate normal RNA exons that supplant the mutated ones during splicing, thereby yielding functional proteins. Additionally, the DNA sequences produce RNA molecules that facilitate the exon editing process.
Robert Bell, a biologist and head of research at Ascidian, highlights the efficacy of the therapy, noting that it can replace 22 exons simultaneously using a single molecule.
Innovative RNA editing for liver cancer treatment
Rznomics, a biopharmaceutical company based in Seongnam, South Korea, is pioneering an RNA editing approach to combat hepatocellular carcinoma, the most prevalent form of liver cancer. Their clinical trial, initiated in September 2022 in South Korea with plans for global expansion, marks a significant advancement in RNA-based therapies beyond genetic disorders.
In contrast to Ascidian’s method, Rznomics utilizes a distinct strategy involving mRNA splicing. Rather than relying on the cell’s native splicing machinery, the company harnesses a naturally occurring ribozyme, an RNA molecule capable of inducing splicing in specific mRNA regions. Engineered ribozymes are designed to cleave open mRNAs within tumor cells and introduce a lethal payload: an RNA sequence translated into a protein that generates a toxin triggering cell death. This therapeutic molecule replaces an RNA sequence associated with tumor proliferation.
According to Lever, Chief Medical Officer of Spliceor in Cambridge, UK, a company specializing in RNA-splicing therapies, the versatility of the splicing approach across various diseases is immensely promising. Lever emphasizes the profound implications of such therapies, remarking that they introduce a breadth of treatment possibilities previously inaccessible.
And now, as requested, let’s close this section with a nod to another groundbreaking gene-editing technology: CRISPR.
Resources
- JOURNAL Lenharo, M. (2024). RNA-editing technologies enter clinical trials. Nature. [Nature]
Cite this page:
APA 7: TWs Editor. (2024, February 19). CRISPR: The Rise of RNA-Editing Treatments. PerEXP Teamworks. [News Link]
