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(GIST OF SCIENCE REPORTER) Therapeutic RNA Editing in Humans

(DECEMBER-2024)

Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency.

WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) that was developed with Wave’s best-in-class oligonucleotide chemistry platform.
It is uniquely designed to address AATD-related lung disease, liver disease, or both.

The role of RNA in a function called RNA interference, where small RNA molecules keep a gene from being expressed, has been essential for the success of CRISPR-Cas9 gene-editing.
The rapid development of mRNA vaccines during the COVID-19 pandemic exemplified the complex as well as vital role RNAs play beyond gene expression and regulation.
Cells synthesise 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. Many of these proteins have been known to cause debilitating disorders.
- RNA editing allows scientists to fix mistakes in the mRNA after the cell has synthesised it but before the cell reads it to make the proteins.

It is a technique used for RNA editing.
Adenosine is one of the building blocks of RNA. ADAR works by converting some of the adenosine blocks in mRNA to another molecule called inosine.
This is useful because inosine mimics the function of a different RNA building block called guanosine.
Because guanosine-like function is found where adenosine is supposed to be, the cell detects a mistake and proceeds to correct it, in the process restoring the mRNA’s original function. And then the cell makes normal proteins.

Scientists took advantage of ADAR’s effects to pair it with a guide RNA (or gRNA): the gRNA guides ADAR to a specific part of the mRNA, where the ADAR works its magic.
Scientists expect a variety of serious genetic conditions that can be treated using such site-specific RNA editing.

RNA Editing by Wave Life Sciences Wave Life Sciences used RNA editing to treat α-1 antitrypsin deficiency (AATD), an inherited disorder. In its therapy, dubbed WVE-006, the company used a gRNA to lead ADAR enzymes to specific single-point mutations in the mRNA sequence of the SERPINA1 gene, which contains the instructions for cells to make α-1 antitrypsin.

A single-point mutation occurs when a single building block of the mRNA is wrong.
Once at the target, the ADAR enzymes fix the mRNA and the cells produce α-1 antitrypsin at normal levels. Wave Life Sciences is planning to extend its RNA editing technology to treat Huntington’s disease, Duchenne muscular dystrophy, and obesity.

Some other companies using ADAR enzymes to perform RNA editing Korro Bio for AATD and Parkinson’s disease ProQr Therapeutics for heart disease and bile acid build-up in the liver Shape Therapeutics for neurological conditions Ascidian Therapeutic is testing its candidate to treat ABCA4 retinopathy.
Researchers are also extending RNA editing to make changes in the exon.
mRNA is made up of portions called introns and exons, exons eventually code for a protein whereas the introns are non-coding parts and are removed from the RNA before it’s used to make a protein.

RNA editing has some advantages over DNA editing, especially on 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.

This is useful for people who require repeated treatment and/or who have immune sensitivities.

Specificity of RNA Editing

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.
Scientists are currently trying to improve the accuracy of gRNA by incorporating mechanisms that shield non-targeted parts of the mRNA.