What is the mechanism of Patisiran sodium?

Patisiran sodium is an innovative therapeutic agent used in the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis), a debilitating genetic disorder. The mechanism of action of Patisiran sodium is rooted in the principles of RNA interference (RNAi), a natural process that cells use to regulate the activity of specific genes. To understand how Patisiran sodium works, it is essential to grasp the basics of RNAi and the pathological basis of hATTR amyloidosis.

hATTR amyloidosis is caused by mutations in the transthyretin (TTR) gene, which leads to the production of misfolded TTR proteins. These misfolded proteins aggregate and form amyloid fibrils that deposit in various tissues and organs, causing progressive damage and dysfunction. The clinical manifestations of hATTR amyloidosis can include neuropathy, cardiomyopathy, and other systemic complications, significantly impairing the quality of life and reducing life expectancy.

Patisiran sodium targets the source of the problem: the production of the mutant TTR protein. It employs RNAi to silence the expression of the TTR gene, thereby reducing the levels of both mutant and wild-type TTR proteins in the bloodstream. Here’s a step-by-step explanation of the mechanism of Patisiran sodium:

1. **Introduction into the Body**: Patisiran sodium is administered via intravenous infusion. Upon administration, it is encapsulated in lipid nanoparticles to enhance delivery to the liver, where TTR is primarily produced.

2. **Delivery to the Liver**: The lipid nanoparticles facilitate the targeted delivery of Patisiran sodium to hepatocytes (liver cells). This targeted approach ensures that the drug reaches the site where TTR protein synthesis predominantly occurs.

3. **RNA Interference Activation**: Once inside the hepatocytes, Patisiran sodium releases small interfering RNA (siRNA) molecules. These siRNA molecules are designed to be complementary to the messenger RNA (mRNA) transcripts produced by the TTR gene.

4. **mRNA Degradation**: The siRNA molecules bind to the TTR mRNA, forming a complex that is recognized by the RNA-induced silencing complex (RISC). This complex cleaves the TTR mRNA, leading to its degradation. Without the mRNA template, the ribosomes in the cell cannot synthesize the TTR protein.

5. **Reduction of TTR Protein**: By degrading the TTR mRNA, Patisiran sodium effectively reduces the synthesis of both mutant and wild-type TTR proteins. As a result, the overall levels of TTR protein in the blood are significantly lowered.

6. **Prevention of Amyloid Formation**: With reduced levels of TTR protein, there is a corresponding decrease in the formation of amyloid fibrils. This ameliorates the deposition of amyloid in tissues and organs, thereby mitigating the pathological damage associated with hATTR amyloidosis.

The clinical efficacy and safety of Patisiran sodium have been demonstrated in clinical trials, where patients treated with the drug exhibited significant improvements in neuropathy symptoms, quality of life, and overall survival compared to those receiving placebo. These benefits are directly attributed to the reduction in TTR protein levels and the consequent decrease in amyloid deposits.

In summary, Patisiran sodium leverages the natural RNAi pathway to specifically target and silence the TTR gene, reducing the production of the pathogenic TTR protein responsible for hATTR amyloidosis. By addressing the root cause of the disease, Patisiran sodium offers a disease-modifying treatment option for patients suffering from this severe genetic disorder.