RNA interference (RNAi) therapy is a medical approach that precisely targets and turns off specific genes contributing to illness. This strategy addresses diseases at their molecular source, rather than just managing symptoms. It leverages natural cellular processes to prevent the production of disease-causing proteins.
Understanding RNA Interference
Cells naturally regulate gene expression through a biological process called RNA interference. This mechanism involves small RNA molecules that inhibit gene expression by degrading specific messenger RNA (mRNA) molecules, preventing protein production. It also plays a role in defending cells against parasitic nucleic acid sequences, such as those from viruses, and influences the normal development of organisms.
The RNAi pathway begins when double-stranded RNA (dsRNA) molecules enter a cell. An enzyme called Dicer cleaves these long dsRNA molecules into smaller fragments, approximately 20-25 nucleotides in length, known as small interfering RNAs (siRNAs) or microRNAs (miRNAs). These small RNA fragments are then incorporated into a protein complex called the RNA-induced silencing complex (RISC).
Once loaded into RISC, one strand of the siRNA, known as the guide strand, remains bound. This guide strand directs the RISC complex to locate and bind to a complementary mRNA molecule. Upon binding, the RISC complex, often with the help of the Argonaute protein, cleaves and degrades the targeted mRNA, preventing it from being translated into a protein.
How RNAi Therapy Works
Scientists harness the natural RNAi mechanism for therapeutic purposes by designing specialized RNA molecules to “silence” disease-causing genes. This engineered approach involves introducing synthetic short interfering RNAs (siRNAs) or microRNAs (miRNAs) into cells. These synthetic RNA molecules are crafted to precisely match the sequence of a problematic messenger RNA (mRNA) that carries instructions for producing an unwanted protein.
When these therapeutic siRNAs or miRNAs enter a cell, they interact with the RNA-induced silencing complex (RISC). The synthetic RNA guides the RISC to the specific target mRNA. For siRNAs, this leads to the direct cleavage and degradation of the target mRNA, effectively stopping the production of the harmful protein.
This process is precise, as the synthetic RNA is designed to bind only to its complementary mRNA sequence. By preventing the translation of disease-associated mRNA into protein, RNAi therapy can halt or reverse the progression of a condition. The catalytic nature of RISC means that a single siRNA-loaded complex can degrade many copies of the target mRNA, leading to a substantial reduction in the problematic protein.
Current and Emerging Applications
RNAi therapy is being applied across various medical fields, with several treatments already approved and many more in development. In 2018, patisiran (Onpattro) became the first FDA-approved RNAi therapeutic, used to treat hereditary transthyretin-mediated amyloidosis (hATTR), a condition involving the accumulation of misfolded proteins that damage nerves and organs.
Following patisiran, givosiran (Givlaari) was approved in 2019 for acute hepatic porphyria (AHP), a rare genetic disorder affecting the nervous system and liver. Lumasiran (Oxlumo), approved in 2020, targets primary hyperoxaluria type 1 (PH1), a rare genetic disease leading to kidney and liver damage. Inclisiran (Leqvio), approved in 2021, is used for hypercholesterolemia, a condition characterized by high cholesterol levels.
Beyond these approved drugs, RNAi therapeutics are being explored for a wide range of other conditions. These include various liver diseases like nonalcoholic fatty liver disease, viral hepatitis, and liver cirrhosis. The technology is also being explored for treating certain cancers by targeting genes associated with tumor growth. RNAi therapies are also being investigated for infectious diseases, including HIV, hepatitis, and influenza, by inhibiting viral replication.
Navigating Development and Application
Delivering RNAi therapies to target cells within the body requires specialized systems. Naked RNA molecules are susceptible to degradation by enzymes in the bloodstream and have difficulty entering cells due to their negative charge. Specialized delivery systems are therefore utilized to overcome these biological barriers.
Lipid nanoparticles (LNPs) are a widely used delivery method, encapsulating the RNA molecules within a protective lipid shell. This protects the RNA from degradation and helps it enter target cells, particularly those in the liver. Viral vectors, such as lentiviruses, are another delivery approach, carrying genetic material that instructs cells to produce the therapeutic RNA molecules internally.
Researchers also work to ensure the specificity of RNAi therapies, aiming to minimize unintended effects on non-target genes. The stability of RNA molecules in the body is enhanced, and immune responses triggered by foreign RNA are managed. Chemical modifications to the RNA molecules themselves can improve stability, reduce immune activation, and enhance delivery to specific tissues.