What is RNA Interference?
RNA interference (RNAi) is a natural, fundamental process within living cells that regulates gene expression by inhibiting the activity of specific genes. The discovery and application of this mechanism earned the Nobel Prize in Physiology or Medicine in 2006, highlighting its profound importance in biology and medicine. In simple terms, genes in our DNA are transcribed into messenger RNA (mRNA) molecules, which then serve as a blueprint for creating proteins. RNAi effectively intercepts this process by destroying the specific mRNA before it can be translated into a protein.
The RNAi process involves several key steps and components:
- Small Interfering RNA (siRNA): Double-stranded RNA molecules, like the active ingredient in ONPATTRO (patisiran), are introduced to the cell.
- RISC Complex Formation: The siRNA is incorporated into a multi-protein complex called the RNA-induced silencing complex (RISC), which contains enzymes capable of cleaving RNA.
- Target mRNA Cleavage: The RISC uses one strand of the siRNA as a guide to locate and bind to a complementary target mRNA sequence.
- Gene Silencing: Once bound, the RISC cleaves and destroys the target mRNA, effectively 'silencing' the gene and preventing the synthesis of the corresponding protein.
How ONPATTRO Specifically Silences the TTR Gene
In patients with hereditary transthyretin-mediated (hATTR) amyloidosis, a genetic mutation causes the liver to produce a misfolded transthyretin (TTR) protein. This abnormal protein accumulates into amyloid deposits, which can cause severe nerve damage (polyneuropathy) and affect vital organs like the heart. ONPATTRO directly targets the root cause of this disease by utilizing RNAi technology to silence the gene responsible for producing TTR.
ONPATTRO (patisiran) is specifically designed to be delivered to liver cells, the primary site of TTR production. The medication encases the siRNA in lipid nanoparticles (LNPs), which are tiny, protective spheres that ensure the siRNA reaches its target intact. Once inside the liver cell, the patisiran siRNA leverages the cell's natural RNAi pathway to bind to and degrade the TTR mRNA. By destroying the TTR mRNA blueprint, ONPATTRO dramatically reduces the amount of both the mutant and wild-type TTR protein in the bloodstream, halting the formation of new amyloid deposits.
Comparison of RNAi Therapies: ONPATTRO vs. Other Approaches
ONPATTRO's approach is distinct from earlier strategies for treating hATTR amyloidosis. Historically, treatments focused on symptom management or stabilizing the misfolded protein. ONPATTRO represents a shift to addressing the genetic origin of the disease. The following table illustrates the different mechanisms of various hATTR treatments.
| Feature | ONPATTRO (Patisiran) | TTR Stabilizers (e.g., Tafamidis) | Antisense Oligonucleotides (e.g., Inotersen) |
|---|---|---|---|
| Mechanism | RNA interference (siRNA) degrades TTR mRNA. | Stabilizes the TTR protein to prevent misfolding. | Antisense oligonucleotide binds and degrades TTR mRNA. |
| Level of Action | Targets the mRNA transcript, preventing protein synthesis. | Acts on the fully-formed TTR protein. | Targets the mRNA transcript, preventing protein synthesis. |
| Effect on TTR Production | Reduces TTR production at the source (liver). | Does not reduce the production of TTR protein. | Reduces TTR production at the source (liver). |
| Administration | Intravenous (IV) infusion every 3 weeks. | Oral capsule once daily. | Subcutaneous injection once per week. |
The Clinical Impact of a Silencer Therapy
For patients suffering from hATTR amyloidosis with polyneuropathy, the clinical impact of a therapy like ONPATTRO is significant. By reducing the supply of the amyloid-forming TTR protein, it can slow or halt the progression of nerve damage and improve neurological function. Clinical trials have shown that patients receiving ONPATTRO experienced improvements in neuropathy impairment scores and quality of life measures compared to placebo. Furthermore, patisiran has demonstrated potential benefits for cardiac function in patients with heart involvement. The treatment requires intravenous infusions administered by a healthcare professional every three weeks, with premedications given to minimize the risk of infusion-related reactions.
The Broader Significance of RNAi-Based Medications
ONPATTRO's success established a new class of RNAi drugs capable of targeting the genetic drivers of disease. It demonstrated that delivering and activating siRNA in humans was both feasible and effective for therapeutic purposes, which was a significant hurdle in the development of gene-silencing technology. Since its approval, other siRNA therapies have followed for different genetic diseases, validating the RNAi platform for developing novel and effective treatments. This advancement represents a fundamental shift in pharmacology, moving beyond symptom management to address the core genetic instructions that cause the disease in the first place.
Conclusion
In summary, the answer to the question, "Is ONPATTRO a silencer?" is a definitive yes. As the first-of-its-kind RNAi therapeutic, ONPATTRO employs a gene-silencing mechanism to target and degrade the messenger RNA that encodes the TTR protein. By effectively preventing the production of the abnormal protein that causes hATTR amyloidosis, this innovative medication offers a fundamentally new treatment paradigm for a devastating genetic disease. The success of ONPATTRO has not only brought new hope to patients with hATTR but has also paved the way for the development of future gene-silencing medications in pharmacology.
