Resolving the Side Effect issue with siRNA Medications for the Treatment of Genetic Diseases

Issue with siRNA Medications for the Treatment of Genetic Diseases

A family of therapeutic medications known as small interfering RNA (siRNA) therapies works by silencing particular genes linked to hereditary disorders. Drugs utilising siRNAs, however, have difficulties because siRNAs frequently mute genes other than the target genes, leading to adverse effects.

 

             CRredit: Mohammed Haneefa

A team from Nagoya University in Japan has managed to chemically modify siRNA to lower the possibility of severe side effects, enhancing the safety of siRNA medications for genetic therapy. Nucleic Acids Research published the findings. 

Short, double-stranded RNAs are known as siRNAs. The messenger RNA (mRNA) of the target, which is the blueprint for proteins, is interacting with siRNAs to prevent their expression. siRNAs have the potential to heal a variety of genetic illnesses by silencing the byproducts of damaging genes, such as proteins that cause disease.

 
On the other hand, off-target effects—which happen when siRNAs interact with non-target mRNA strands—reduce the therapeutic potential of siRNA. These inadvertent encounters may result in deleterious modifications to vital genes, upsetting cellular functions and weakening the immune system. 

The seed region, a seven-nucleotide region essential for target recognition that is situated within the siRNA's guide strand, is a major contributor to these off-target effects. The seed region sequence typically forms base pairs with non-target mRNA strands, which leads to off-target effects.

 
According to Professor Hiroshi Abe, "the off-target effect probably happens when non-target mRNAs exist that form base pairs with the seed region of siRNA." "We realised that the off-target effect could be suppressed by reducing the base pairing ability or double-strand stability in this seed region using chemical modification, ensuring that a stable complex is formed only when the entire guide strand binds to the target mRNA." 

To alter the siRNA at this crucial area, the team lead by Professor Abe and his pupil Kohei Nomura employed a formamide modification. Hydrogen bond formation can be inhibited by formamide groups.
Hydrogen bonding between complementary bases are necessary for the double helix to remain stable in mRNA.

Formamide disrupts these hydrogen bonds, destabilising the mRNA's helical form and resulting in denaturation, or the separation of the strands. The likelihood of off-target effects is decreased because binding to the seed area of siRNA is challenging in the absence of strand synthesis.

"This modification achieved suppression of off-target effects with higher efficiency than existing chemical modifications," Abe stated. "Introduction of the modification at a single location achieved the desired effect, enabling a highly flexible sequence design of siRNA."

 
With this alteration, chemically altered siRNAs are anticipated to be used as less side effecting siRNA medications. Nomura thinks the study could lead to siRNA treatments for conditions like mixed dyslipidaemia, primary hypercholesterolaemia, acute hepatic porphyria, inherited transthyretin amyloidosis, and primary hyperoxaluria type 1.