Introduction
The small interfering RNA (siRNA) discovered in the late 1990s opened new avenues in molecular biology.
SiRNA is a type of double-stranded RNA that works by selectively silencing specific genes via RNA interference pathways.
The discovery of siRNA significantly improved our understanding of molecular mechanisms behind gene regulation.
Now, scientists are redesigning siRNA as a powerful tool for treating various genetic diseases.
Mechanism of siRNA
siRNA works through a sophisticated molecular mechanism called RNA interference (RNAi).
First, small segments of siRNA molecules are formed from large double-stranded RNA and are associated with the RNA-induced silencing complex (RISC).
This large protein complex (RISC) guided by siRNA then attacks messenger RNA (mRNA), another RNA molecule responsible for carrying genetic information from DNA to protein-making ribosomes in cells.
siRNA-guided RISC cleaves the mRNA, preventing the formation of proteins and thereby effectively silencing the gene from which the mRNA was produced.
The main advantage of siRNA is its high specificity compared to other gene-silencing RNA molecules like microRNA (miRNA) or piwi-interacting RNA (piRNA).
Scientists can modify siRNA sequences in research laboratories to make it cleave any mRNA molecules.
Also, it precisely silences the genes by targeting desired mRNA sequences with near-perfect complementarity.
This specificity makes siRNA an invaluable tool in scientific research, specifically in creating RNA-based therapies that can silence specific genes responsible for diseases.
Therapeutic Applications of siRNA
siRNA-based therapies have shown significant promise in medical science, mainly for treating various genetic and viral conditions.
Researchers can now design custom siRNA that can specifically target and silence disease-causing mutated genes or viral genomes, thereby halting disease progression.
siRNA-based therapeutics have been tested in many conditions, including genetic diseases like hereditary transthyretin-mediated amyloidosis (hATTR), as well as viral diseases like HIV, respiratory syncytial virus (RSV), and hepatitis B.
Eplontersen is a new siRNA-based medicine developed by AstraZeneca and Ionis Pharmaceuticals. It is approved by the US Food and Drug Administration (FDA) for treating hATTR (Hereditary transthyretin-mediated amyloidosis).
hATTR is a genetic disorder characterized by a mutation in the TTR (transthyretin) gene and subsequent accumulation of misfolded transthyretin protein, which can lead to severe damage to nerves, the heart, and other organs.
Eplontersen acts by targeting and silencing the TTR gene’s mRNA, thereby significantly reducing the accumulation of transthyretin protein. This, in turn, has shown remarkable efficacy in halting disease progression and improving patients’ quality of life.
Moreover, Alnylam Pharmaceuticals’ ONPATTRO, which was approved by the US FDA for the management of the polyneuropathy of hATTR amyloidosis in adults, is another siRNA-based therapeutic hoping to hit the market soon.
In addition, Inclisiran, developed by Novartis for the medical treatment of hypercholesterolemia, is another milestone in siRNA-based medicines.
This medicine, inclisiran, exerts its actions by selectively silencing the PCSK9 gene (the gene responsible for regulating the amount of cholesterol in the blood), thereby lowering the level of LDL cholesterol in the patient’s blood.
Challenges of siRNA-Based Therapeutics
Many barriers must be adequately addressed to harness the therapeutic potential of siRNA-based therapeutic technology fully.
One such challenge is the precise and site-specific delivery of siRNA molecules into desired cells and tissues where it is needed.
The crucial aspects that modulate and influence the therapeutic effectiveness of siRNA include its stability in circulation, its ability to cross the plasma membrane of cells, and its escape from the cellular endosomal compartments.
Researchers are developing innovative strategies to tackle these obstructions, including producing nanoparticle-based carrier systems that protect siRNA from damage, facilitate cellular entry and ensure their delivery into the cytoplasm, where they can interact with RNAi machinery.
Lipid nanoparticles have recently emerged as promising delivery vehicles for siRNA due to their ability to encapsulate siRNA molecules, protect them from nuclease destruction and facilitate their cellular uptake by target cells.
Another challenge associated with siRNA-based therapies is the off-target effects of siRNAs.
Although siRNA allows for precise gene silencing, sometimes these RNA molecules silence genes other than the intended target genes.
To minimize the risk of off-target effects, scientists are utilizing advanced mathematical models, computational tools, and experimental techniques to develop siRNA sequences that are highly specific to only their target mRNA.
Many regulatory and manufacturing challenges are associated with integrating siRNA therapies into clinical practice.
Getting FDA approval for a therapeutic application is complex and involves rigorous examination for safety, efficacy, and quality.
The crucial steps that require substantial funding and expertise in siRNA-based therapy are producing siRNA-based drugs at a large scale, ensuring their quality and uniformity, and developing appropriate formulations for their delivery.
Future Prospects of siRNA-Based Therapeutics
The future potential of siRNA technology in medicine is vast.
SiRNA-based therapeutics provide an effective strategy for treating a wide range of diseases, specifically those that cannot be efficiently or readily managed with therapeutic medicines.
Current research and development in siRNA therapy have led to better and safer treatment plans, which can greatly improve patient outcomes and quality of life.
The ongoing research concentrates on optimizing the transport and specificity of siRNA molecules.
Scientists around the world are utilizing their understanding of siRNA to develop therapies for various diseases, such as cancer, metabolic disorders, and neurodegenerative conditions.
Several siRNA-based therapies are being created and evaluated in various stages of development and clinical trials.
Companies like AstraZeneca, Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Sanofi are at the forefront of this medical revolution, pushing the boundaries with their novel siRNA-based therapeutics.
Joint efforts and strategic alliances between biotech firms, pharmaceutical companies, and research institutions are essential for the rapid development and commercialization of siRNA technology by combining expertise and resources.
These partnerships promote the sharing of knowledge and technologies and boost their ability to overcome complex regulatory, manufacturing, and commercialization hurdles.
Conclusion
In conclusion, siRNA-based therapeutics represent a modern tool in personalized medicine with the potential to transform how many diseases are managed by addressing their genetic roots.
Given advancements in scientific research and technological innovations, medical treatments based on small interfering RNA (siRNA) are expected to play a more critical role in future medical practice.
With the collaborative effects of scientists, clinicians and pharmaceutical companies, the future of siRNA in medicine looks promising, paving the way for a new era of individualized treatment approaches.
