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Breakthrough in RNA Editing
Context:
Wave Life Sciences, a biotechnology company based in Massachusetts, made history by becoming the first to treat a genetic condition through clinical RNA editing.
- The company’s therapy, WVE-006, targets α-1 antitrypsin deficiency (AATD), an inherited disorder that affects the liver and lungs.
What is RNA Editing?
- RNA editing is a process that allows scientists to make targeted corrections in messenger RNA (mRNA), the molecule that transmits genetic instructions from DNA to the cellular machinery that makes proteins.
- The mRNA is synthesised based on DNA instructions, but sometimes errors can occur during this process, leading to faulty proteins that can cause diseases.
- RNA editing aims to fix these errors before the mRNA is used to produce proteins, offering a potential treatment option for many genetic disorders.
Wave Life Sciences’ RNA Editing for AATD:
- α-1 antitrypsin deficiency (AATD) is a genetic disorder in which abnormal levels of the protein α-1 antitrypsin damage the liver and lungs.
- Wave Life Sciences used RNA editing to correct a single-point mutation in the SERPINA1 gene, which is responsible for producing this protein.
- The therapy, WVE-006, helps patients produce normal levels of α-1 antitrypsin, offering a potential alternative to weekly intravenous treatments or, for those with liver damage, a liver transplant.
RNA Editing Working:
- ADAR enzymes (adenosine deaminase acting on RNA) play a central role. They convert adenosine (one of the building blocks of RNA) into inosine, which mimics another building block, guanosine.
- This trick allows the cell to detect a “mistake” in the RNA sequence, leading it to correct the error and produce the correct protein.
- In clinical applications, guide RNA (gRNA) directs ADAR enzymes to specific mutations in the mRNA, allowing for targeted editing.
Applications of RNA Editing:
- Huntington’s disease, Duchenne muscular dystrophy, and certain types of obesity—all associated with single-point mutations—are among the next targets for RNA editing treatments.
- Other Companies Exploring RNA Editing:
- Korro Bio is developing RNA editing treatments for AATD and Parkinson’s disease.
- ProQr Therapeutics is targeting heart disease and bile acid buildup in the liver.
- Shape Therapeutics is working on neurological conditions.
- Extending RNA Editing: T o include changes in exons (coding regions of mRNA), as opposed to just correcting single-point mutations.
- Ascidian Therapeutics is testing RNA editing as a treatment for ABCA4 retinopathy, a type of eye disease caused by mutations in the ABCA4 gene.
- Rznomics, a South Korean company, has also been granted permission to conduct RNA editing trials in the U.S. for liver cancer, focusing on regulating telomerase reverse transcriptase to prevent tumour formation.
Challenges:
- Specificity and Precision: ADAR enzymes may affect both the intended and unintended parts of the mRNA, leading to potential off-target effects or skipping the intended mutation altogether.
- To address this, researchers are refining gRNA to improve accuracy and reduce unwanted modifications.
- Transient Nature: While the temporary nature of RNA editing is an advantage, it also means that repeated treatments may be necessary to maintain therapeutic benefits.
- Delivery Methods: Lipid nanoparticles and adeno-associated virus (AAV) vectors are the current methods used to deliver gRNA and ADAR enzymes to cells.
- However, both methods have limited capacity for carrying large molecules, which could hinder the delivery of complex RNA editing systems to the target cells effectively.
Future Outlook:
- RNA editing is in its early stages, but at least 11 biotech companies are working on RNA editing techniques for various diseases.
- Interest from major pharmaceutical companies like Eli Lilly, Roche, and Novo Nordisk indicates growing investment in this technology.
- As clinical trials progress, RNA editing could become an integral part of precision medicine, offering treatments for a range of genetic disorders that were previously considered incurable.
Conclusion:
Wave Life Sciences’ use of RNA editing to treat α-1 antitrypsin deficiency represents a significant breakthrough in biotechnology and gene therapy. By addressing genetic disorders at the level of mRNA, RNA editing offers a safe, temporary, and targeted solution that could change the lives of millions of patients worldwide.
RNA Editing vs. DNA Editing
- RNA editing has several advantages over traditional DNA editing technologies, such as CRISPR-Cas9.
- While DNA editing permanently alters the genome, RNA editing only makes temporary changes to mRNA. This means the effects of RNA editing can fade over time, offering a safety advantage.
- If any issues arise during RNA editing therapy, doctors can stop treatment, and the body can return to its normal state without irreversible genomic changes.
- Furthermore, CRISPR-Cas9 often rely on proteins derived from bacteria, which can trigger immune reactions. RNA editing, on the other hand, uses ADAR enzymes, which naturally occur in the human body and are less likely to cause allergic responses.
