siRNA therapy is a medical strategy designed to address diseases at their genetic origin. This approach involves precisely “silencing” or “turning down” specific genes responsible for illness. It acts like a highly specific dimmer switch, controlling the activity of a faulty gene within the body. This therapy offers a targeted way to intervene in disease processes, aiming to correct underlying genetic malfunctions rather than merely managing symptoms.
The Mechanism of Gene Silencing
Genetic information flows from DNA, the body’s blueprint, to messenger RNA (mRNA), which carries instructions for building proteins. These mRNA molecules are then translated into proteins that perform various functions. Many diseases arise when faulty proteins are produced due to errors in this pathway.
Small interfering RNA (siRNA) intervenes as a targeted inhibitor. It is a small, double-stranded RNA, typically 20-25 nucleotides long, engineered to precisely match a problematic mRNA segment. Inside a cell, siRNA integrates into the RNA-induced silencing complex (RISC). The RISC unwinds the siRNA, retaining one strand (the guide strand) that directs the complex to its target.
The guide strand, now part of the RISC, searches for and binds to the complementary target mRNA sequence. This highly specific binding ensures only the intended mRNA is recognized. Upon binding, the RISC complex, equipped with an Argonaute protein, cleaves and degrades the target mRNA molecule. This prevents the mRNA from being translated into the faulty protein, effectively silencing the gene and halting the production of the disease-causing agent.
Developing and Delivering siRNA Drugs
Turning siRNA molecules into effective therapies presents challenges due to their fragility and difficulty entering cells. Unprotected siRNA is susceptible to rapid degradation by bloodstream enzymes and struggles to cross cell membranes. Overcoming these barriers requires specialized delivery systems that protect siRNA and facilitate its entry into specific cells.
Lipid Nanoparticles (LNPs) are a widely used delivery method. These tiny spherical structures, composed of various lipids, encapsulate siRNA, shielding it from enzymatic breakdown. LNPs are taken up by cells, often through endocytosis. Once inside, the LNP facilitates siRNA release into the cytoplasm, where it engages with the RNA interference machinery. This technology is also used in mRNA COVID-19 vaccines.
Another strategy involves conjugating siRNA to a specific targeting ligand. N-acetylgalactosamine (GalNAc) is a prominent example. This sugar molecule binds to the asialoglycoprotein receptor (ASGPR), a protein abundant on liver cells (hepatocytes). This binding triggers receptor-mediated endocytosis, allowing the siRNA-GalNAc conjugate to be efficiently internalized by liver cells. This system ensures precise delivery to the liver, making it an effective approach for treating liver-related conditions.
Approved Treatments and Targeted Conditions
siRNA therapy has transitioned from concept to tangible treatments, offering new options for various conditions.
Patisiran (Onpattro) was the first RNA interference therapeutic approved globally for hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy in adults. This rare, progressive condition involves a mutated transthyretin (TTR) protein, primarily from the liver, misfolding and accumulating as amyloid deposits in nerves and other organs. Patisiran degrades TTR mRNA, reducing TTR protein production, which lessens amyloid deposits and improves nerve function.
Givosiran (Givlaari) is approved for acute hepatic porphyria (AHP) in adults. AHP is a group of rare genetic disorders caused by enzyme deficiencies in the liver’s heme biosynthesis pathway, leading to neurotoxic precursor accumulation. Givosiran silences the messenger RNA for aminolevulinate synthase 1 (ALAS1), the enzyme responsible for overproduction of these precursors, thereby reducing attack frequency and severity.
Lumasiran (Oxlumo) is an approved siRNA therapeutic for primary hyperoxaluria type 1 (PH1) in pediatric and adult patients. PH1 is an ultra-rare genetic disease where an enzyme deficiency causes the liver to overproduce oxalate. This leads to calcium oxalate crystal formation in the kidneys and urinary tract, potentially causing kidney stones, nephrocalcinosis, and kidney failure. Lumasiran targets the messenger RNA for hydroxyacid oxidase 1 (HAO1), an enzyme involved in oxalate production, reducing oxalate levels and mitigating disease progression.
Inclisiran (Leqvio) is approved for lowering high cholesterol. This therapy targets proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver protein that regulates low-density lipoprotein (LDL) receptors on liver cell surfaces. PCSK9 normally degrades these receptors, reducing the liver’s ability to clear LDL cholesterol. By silencing PCSK9 mRNA, inclisiran reduces PCSK9 protein, allowing more LDL receptors to remain and enhancing LDL cholesterol removal from the bloodstream.
Current Research and Clinical Trials
The field of siRNA therapy continues to expand, with active research exploring its application across a broader spectrum of diseases. Clinical trials are evaluating siRNA molecules for neurodegenerative conditions, aiming to address their underlying genetic causes. For instance, studies are investigating siRNAs designed to reduce levels of mutant huntingtin protein, associated with Huntington’s disease.
siRNA therapies are also being explored for various viral infections, particularly those with chronic implications. Hepatitis B virus (HBV) is a target, with several siRNA candidates in clinical trials designed to silence viral genes and reduce the production of viral antigens like hepatitis B surface antigen (HBsAg). These investigational therapies aim to offer sustained viral suppression and potential functional cures for chronic infections.
siRNA technology is also being tested in cancer treatment. Researchers are investigating siRNAs that can target genes promoting tumor growth, metastasis, or drug resistance. Clinical trials involve delivering siRNA to silence specific oncogenes or pathways, with early-phase studies underway.