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Advancements in siRNA Drug Safety Through Chemical Modifications
Small interfering RNA (siRNA) drugs represent a promising frontier in the treatment of genetic disorders, particularly those inherited through familial lines. These therapeutic agents function by silencing specific genes linked to such diseases. Nonetheless, their clinical application is often hampered by the occurrence of off-target effects, where siRNAs inadvertently silence unintended genes, leading to undesirable side effects. A research team from Nagoya University in Japan has pioneered a method to chemically modify siRNA with formamide, significantly reducing these off-target interactions and enhancing the safety profile of siRNA therapies. Their findings were recently published in the journal Nucleic Acids Research.
siRNAs consist of short, double-stranded RNA fragments that bind to messenger RNA (mRNA), crucial for protein synthesis, thereby obstructing the expression of harmful proteins produced by misregulated genes. This action positions siRNAs as potential treatments for a variety of genetic disorders that stem from faulty gene expression.
Despite their promise, the therapeutic effectiveness of siRNAs is often restricted by off-target effects. These effects arise when siRNAs bind to mRNA sequences that are not their intended targets, which can result in detrimental modifications to vital genes and disrupt critical cellular functions, including immune responses.
A primary contributor to these off-target effects is a region within the siRNA known as the seed region, which comprises seven nucleotides and is essential for the siRNA’s target recognition capabilities. Off-target binding is common due to the seed region’s ability to form complementary base pairs with unintended mRNA strands.
Professor Hiroshi Abe, who leads the research, stated, “Off-target effects are likely when non-target mRNAs can form base pairs with the siRNA’s seed region. We hypothesized that we could mitigate these effects by chemically modifying this region to reduce its base pairing capacity, ensuring stable binding only occurs between the siRNA and its intended mRNA target.”
The team, including graduate student Kohei Nomura, implemented a formamide modification targeting the seed region of the siRNA. Formamide groups serve to disrupt hydrogen bonding, a critical aspect of mRNA’s double-helix stability. By interfering with these hydrogen bonds, formamide causes the mRNA structure to destabilize, leading to denaturation or separation of the strands. This disruption makes it challenging for the siRNA’s seed region to bind improperly, thereby lowering the likelihood of off-target effects.
“Our modification was shown to suppress off-target effects with greater efficiency compared to prior chemical alterations,” Professor Abe noted. “A single modification site yielded our desired outcome, allowing us greater versatility in designing siRNA sequences.”
The implications of this innovative approach are significant. SiRNAs modified in this manner are anticipated to serve as therapies with reduced side effects. Nomura indicated that this research holds promise for developing siRNA treatments targeting conditions such as hereditary transthyretin amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1, primary hypercholesterolemia, and mixed dyslipidemia.
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