RNA Editing Promises to Go Where DNA Editing Can’t

Syllabus: GS3/ Science and Technology

Context

• A biotechnology company, Wave Life Sciences successfully performed the first clinical RNA editing in humans on two patients with alpha-1 antitrypsin deficiency.

What is RNA editing?

• Cells synthesize messenger RNA (mRNA) using instructions in DNA and then ‘read’ instructions from the mRNA to make functional proteins.
  • During this process of transcription, the cell may make mistakes in the mRNA’s sequence and based on it produce faulty proteins. 
• RNA editing is a process where scientists correct errors in mRNA after it’s synthesized by the cell but before it’s read to produce proteins.
  • This helps prevent the production of faulty proteins that can cause disorders.

Adenosine deaminase acting on RNA (ADAR)

• The technique involves a group of enzymes called adenosine deaminase acting on RNA (ADAR). 
• ADAR changes parts of mRNA by turning adenosine into inosine, which acts like guanosine. 
  • This change helps the cell recognize a problem in the mRNA and fix it, allowing the cell to produce normal proteins.
• Scientists use guide RNA (gRNA) to direct ADAR to the specific part of the mRNA that needs editing, ensuring precise corrections.

α-1 Antitrypsin Deficiency (AATD)

• It is an inherited disorder where patients suffering from AATD, levels of the protein α-1 antitrypsin build up and affect the liver and the lungs. 
• People with AATD affecting the lungs currently go through weekly intravenous therapy for relief. 
• Among people where AATD has affected the liver, a liver transplant is the sole treatment option.

RNA v. DNA Editing

• Safety and flexibility: DNA editing makes permanent changes to a person’s genome and sometimes this can lead to irreversible errors.
  • On the other hand, RNA editing makes temporary changes, allowing the effects of the edits to fade over time. 
• CRISPR-Cas9 and other DNA editing tools require proteins acquired from certain bacteria to perform the cutting function, but these proteins can elicit undesirable immune reactions in some cases.
  • RNA editing relies on ADAR enzymes, which already occur in the human body and thus present a lower risk of allergic reactions. 

Challenges in RNA Editing

• Specificity: ADARs can perform adenosine-inosine changes in both targeted and non-targeted parts of mRNA, or skip the targeted parts altogether.
  • When ADARs don’t align with the adenosine of interest, potentially serious side-effects could arise. 
• Transient nature of RNA editing: this is also its strength, but individuals will need to be treated repeatedly to sustain the therapy’s effects.
• Current methods to deliver the gRNA-ADAR complex use lipid nanoparticles. Both these methods have a limited carrying capacity, meaning they can’t transport large molecules very well.

Conclusion

• Although RNA editing is still in its early stages, numerous companies globally are working on developing these methods to treat various diseases. 
• With continued research and clinical trials, RNA editing is poised to become an integral part of the gene-editing toolkit in medical practice.

Source: TH