Small interfering RNA (siRNA) drugs are a new class of medicines that treat diseases by targeting genetic instructions within cells. They harness a natural cellular process to reduce or stop the creation of specific disease-causing proteins. This mechanism distinguishes siRNA drugs from traditional small molecule or antibody-based therapies.
Understanding How siRNA Drugs Function
siRNA drugs function through a natural biological process called RNA interference (RNAi), a process that regulates gene expression. These drugs are short, double-stranded RNA molecules, typically ranging from 19 to 25 base pairs in length. When introduced into a cell, the siRNA molecule is recognized by a protein complex known as the RNA-induced silencing complex (RISC).
The RISC then unwinds the double-stranded siRNA, discarding one strand (the “passenger” strand) and retaining the other (the “guide” strand). This guide strand is complementary to a specific messenger RNA (mRNA) molecule. The RISC then binds to its matching mRNA target.
Once the siRNA-loaded RISC binds to the target mRNA, it acts like molecular scissors, cleaving the mRNA molecule. This degradation prevents the mRNA from being translated into a protein, effectively “silencing” the gene’s expression. A single siRNA-RISC complex can degrade multiple copies of the target mRNA, making this process highly efficient in reducing disease-causing proteins.
Approved siRNA Drug Treatments
Several siRNA drugs have gained regulatory approval for various conditions:
- Onpattro (patisiran), approved in 2018 for hereditary transthyretin-mediated amyloidosis with polyneuropathy, a condition involving abnormal transthyretin protein buildup, which patisiran reduces.
- Givlaari (givosiran), approved in 2019 for acute hepatic porphyria, a rare genetic disorder, lowers levels of delta-aminolevulinate synthase 1 (ALAS1) mRNA, decreasing neurotoxic porphyrin precursors.
- Oxlumo (lumasiran), approved in 2020 for primary hyperoxaluria type 1, a rare genetic disorder, reduces an enzyme involved in oxalate synthesis, helping prevent kidney stones and damage.
- Leqvio (inclisiran), approved in 2021 for high cholesterol in patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia, targets mRNA encoding proprotein convertase subtilisin k9 (PCSK9), an enzyme that degrades LDL receptors, lowering LDL cholesterol.
- Other approved siRNA drugs include Amvuttra (vutrisiran) for hereditary transthyretin-mediated amyloidosis, and Rivfloza (nedosiran) for primary hyperoxaluria type 1.
Overcoming Development Hurdles
Developing siRNA drugs has presented several challenges, particularly concerning their stability and delivery within the body. Naked siRNA molecules are unstable in the bloodstream, susceptible to rapid degradation by enzymes called nucleases, and can be quickly cleared by the kidneys. Furthermore, these exogenous nucleic acid molecules can sometimes trigger an unwanted immune response.
A significant hurdle involves getting the siRNA into the target cells and ensuring it effectively escapes cellular compartments, such as endosomes, to reach its site of action in the cytoplasm. To address these issues, researchers employ various strategies. Chemical modifications to the siRNA molecules enhance their stability, improve binding affinity to their targets, and reduce potential immune activation.
Delivery systems are crucial for successful siRNA therapeutics. Lipid nanoparticles (LNPs) are a widely used approach, encapsulating the siRNA to protect it from degradation and facilitate its entry into cells. Another common strategy, particularly for liver-targeted therapies, involves conjugating the siRNA with N-acetylgalactosamine (GalNAc), which binds to receptors on liver cells, enabling specific uptake. These advancements help ensure the siRNA reaches its intended cellular destination effectively while minimizing off-target effects, which occur when the siRNA interacts with unintended mRNA strands.
New Therapeutic Directions
The field of siRNA therapeutics is actively exploring new applications beyond currently approved treatments, showcasing broad future potential. Researchers are investigating siRNA drugs for various neurological disorders, aiming to silence genes involved in conditions like Alzheimer’s and Parkinson’s diseases. This approach could offer targeted interventions for complex brain diseases.
siRNA technology also holds promise in cancer therapy by targeting oncogenes, which are genes that can contribute to cancer development. Efforts are underway to use siRNAs to overcome drug resistance in cancer and to modulate the tumor microenvironment, potentially offering new avenues for treatment.
Further research focuses on infectious diseases, where siRNAs could target viral RNA to inhibit replication of pathogens such as HIV, influenza, and hepatitis B and C viruses. This gene-silencing mechanism could provide effective antiviral therapies. The ability of siRNA to precisely target any gene with a complementary sequence makes it an attractive tool for addressing a wide range of genetic conditions and other diseases, including those affecting metabolism and the cardiovascular system.