Wave Life Sciences, a Massachusetts-based biotech company, recently became the first to treat a genetic disorder by editing RNA at the clinical level.

• RNA’s role in gene expression and interference, essential for CRISPR-Cas9’s success, has brought it to the forefront of precision medicine.

About RNA Editing

• RNA and Protein Synthesis: Cells produce messenger RNA (mRNA) based on DNA instructions, which then direct protein synthesis. Mistakes in mRNA can result in faulty proteins causing various genetic disorders.
• ADAR Enzyme Role: Adenosine deaminase acting on RNA (ADAR) converts adenosine in mRNA to inosine, which mimics guanosine.
  • This alteration can correct mutations, helping cells produce functional proteins.
• Guide RNA (gRNA): gRNA directs ADAR to specific mRNA sites for targeted corrections, offering a potential treatment for genetic conditions involving single-point mutations.

What are the three types of RNA modifications?

• The three types of RNA modifications are addition, deletion, and substitution.
• Addition is when a nucleotide is inserted. 
• Deletion is when one is removed. 
• And substitution is when one nucleotide is exchanged for another.

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Clinical Application in Treating Genetic Disorders

• WVE-006 Therapy: Wave Life Sciences developed a therapy for α-1 antitrypsin deficiency (AATD), a condition causing liver and lung issues.
  • WVE-006 uses gRNA to guide ADAR enzymes to correct specific single-point mutations in the SERPINA1 gene.
• Potential for Broader Applications: The company is exploring RNA editing for Huntington’s disease, Duchenne muscular dystrophy, and certain forms of obesity, all associated with single-point mutations.

Other Companies in the RNA Editing Field

• Korro Bio: Focuses on RNA editing for AATD and Parkinson’s disease.
• ProQr Therapeutics: Develops treatments for heart disease and bile acid build-up in the liver.
• Shape Therapeutics: Works on RNA editing therapies for neurological disorders.
• Ascidian Therapeutic: Testing RNA editing for ABCA4 retinopathy; the large ABCA4 gene size makes standard gene therapy difficult, making RNA editing a suitable alternative.
• Rznomics: Conducting trials on liver cancer treatments in the U.S. and South Korea, targeting human telomerase reverse transcriptase to reduce tumor growth.

RNA Editing Vs DNA Editing

Challenges in RNA Editing

• Specificity Issues: ADAR enzymes can edit both targeted and non-targeted mRNA parts, potentially leading to unintended effects.
  • Improving gRNA targeting accuracy is a key focus.
• Transient Nature: RNA editing’s temporary effects require repeated treatments for sustained benefits.
• Delivery Limitations: Current delivery methods, like lipid nanoparticles and adeno-associated virus (AAV) vectors, have limited capacity for transporting larger molecules.

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Future of RNA Editing

• RNA editing is in its early stages, with at least 11 companies worldwide developing treatments for a variety of genetic conditions.
• Major pharmaceutical companies, including Eli Lilly, Roche, and Novo Nordisk, have shown significant interest, indicating that RNA editing may soon become a staple in precision medicine.

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