RNA Editing Breakthrough

November 7, 2024

GS Paper III Science and Technology

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 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

Aspect	DNA Editing	RNA Editing
Target Molecule	DNA	RNA
Structure of Molecule	Usually double-stranded; some viruses have single-stranded DNA	Mostly single-stranded; some viruses (e.g., retroviruses) have double-stranded RNA
Sugar Component	Deoxyribose	Ribose
Nucleotide Bases	Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)	Adenine (A), Guanine (G), Cytosine (C), and Uracil (U)
Base Pairing Rules	A pairs with T, G pairs with C	A pairs with U, G pairs with C
Permanency of Edits	Permanent changes in the DNA sequence	Temporary changes in mRNA sequence; effects can fade over time
Specificity	High, but requires precise targeting to avoid permanent off-target mutations	Can be less specific; off-target edits possible if ADAR enzymes modify non-target mRNA parts
Risk of Immune Reaction	Potential immune reactions due to foreign proteins from bacterial sources (e.g., CRISPR-Cas9)	Lower immune risk, as ADAR enzymes used are naturally present in human cells
Genetic Impact	Alters the individual’s genome; changes can be passed onto future cell generations	Alters mRNA temporarily; does not change the genome, thus effects are not heritable
Use of Enzymes	Uses proteins from certain bacteria (e.g., Cas9 in CRISPR) for DNA cutting	Uses ADAR enzymes which convert adenosine (A) to inosine (I), mimicking guanosine (G) function
Safety	It has the risk of permanent damage.	RNA editing’s changes are temporary, allowing effects to fade over time, reducing the risk of permanent errors
Delivery Mechanisms	Often uses viral vectors (e.g., adeno-associated virus)	Typically uses lipid nanoparticles or viral vectors; however, limited capacity for larger molecules
Applications	Used in treating inherited diseases, gene therapy, and modifying agricultural species	Potential treatment for diseases caused by single-point mutations (e.g., Huntington’s, liver cancer)

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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