From the Guidelines
Small interfering RNA (siRNA) is a type of short, double-stranded RNA molecule that plays a crucial role in pathology by specifically silencing gene expression through a process called RNA interference (RNAi). In pathology, siRNAs function by binding to complementary messenger RNA (mRNA) sequences, leading to their degradation and preventing the translation of disease-causing proteins. This mechanism has significant implications for both understanding disease processes and developing therapeutic interventions. siRNAs typically consist of 19-25 nucleotides, as described in the study published in Nucleic Acids Research 1, and work by incorporating into a protein complex called RNA-induced silencing complex (RISC), which then targets and cleaves specific mRNA molecules.
Mechanism of Action
The mechanism of action of siRNA involves the activation of the antisense strand via selective removal of the sense strand by Argonaute 2 (Ago2), an RNA-induced silencing complex (RISC) endonuclease, as outlined in the study 1. The antisense strand then causes RNA silencing by catalyzing the destruction of and/or selectively inhibiting translation of complementary RNA transcript.
Clinical Applications
In pathological contexts, researchers and clinicians utilize siRNAs to investigate gene function in disease models, identify potential therapeutic targets, and develop treatments for various conditions including viral infections, cancer, and genetic disorders. For example, givosiran, an approved siRNA therapeutic, modulates ALAS-1 mRNA transcript levels, highlighting the potential for siRNAs to treat diseases by targeting specific gene expression 1.
Considerations for Therapeutic Use
The specificity of siRNA-mediated gene silencing makes it a powerful tool for targeting disease-specific genes while minimizing off-target effects. However, challenges in delivery to target tissues and potential immune responses remain important considerations in their clinical application. Additionally, the potential for drug-drug interactions (DDIs) mediated by mechanism-based effects or indirect disease-drug interactions should be evaluated for each siRNA on a case-by-case basis, as discussed in the study 1.
Key Points
- siRNAs are short, double-stranded RNA molecules that silence gene expression through RNA interference (RNAi)
- siRNAs function by binding to complementary mRNA sequences, leading to their degradation and preventing the translation of disease-causing proteins
- siRNAs have significant implications for understanding disease processes and developing therapeutic interventions
- Challenges in delivery and potential immune responses are important considerations in clinical application
- The potential for DDIs should be evaluated for each siRNA on a case-by-case basis
From the Research
Definition and Mechanism of siRNA
- Small interfering RNA (siRNA) is a type of RNA that plays a key role in the regulation of gene expression by interfering with the expression of specific genes 2, 3.
- siRNA works by binding to specific complementary messenger RNA (mRNA) molecules, which are then degraded, resulting in the silencing of the expression of the corresponding gene 3, 4.
- The mechanism of action of siRNA is based on post-transcriptional gene silencing, which allows for the specific and efficient knockdown of disease-related genes 4.
Therapeutic Applications of siRNA
- siRNA has emerged as a promising therapeutic approach for the treatment of various diseases, including viral infections, genetic diseases, and cancer 2, 5, 6.
- siRNA-based therapies have shown potential in reducing the expression of disease-associated genes and have been used to develop treatments for diseases such as hereditary transthyretin-mediated amyloidosis, acute hepatic porphyria, and primary hyperoxaluria type 1 3.
- siRNA therapy offers advantages over other therapeutic approaches, including the ability to specifically target any mRNA and improved patient adherence due to infrequent administration and long duration of action 3.
Challenges and Limitations of siRNA Therapy
- Despite the promising therapeutic benefits of siRNA, several challenges and limitations need to be overcome, including impaired long-term protein expression, siRNA instability, off-target effects, immunological responses, and drug resistance 2, 3, 4.
- The delivery of siRNA to target cells is a major challenge, and various carrier systems, such as cationic polymers, have been designed to protect siRNA from degradation and facilitate its delivery to the cytosol of target cells 5, 4.
- Ongoing challenges remain in targeting organs beyond the liver and reaching special sites, such as the brain, but technological advances are paving the way for broader clinical use of siRNA therapy 3.