Onpattro (patisiran) works by using a natural cellular process called RNA interference to shut down production of a specific protein that causes nerve damage. It was the first FDA-approved therapy based on this technology, and it targets the root cause of hereditary transthyretin amyloidosis (hATTR) rather than just managing symptoms.
The Disease Onpattro Treats
To understand how Onpattro works, it helps to know what’s going wrong in the body. In hATTR amyloidosis, a genetic mutation makes the liver produce an unstable version of a protein called transthyretin (TTR). Normally, TTR circulates in the blood as a stable four-part structure and carries vitamin A and thyroid hormones. But in people with hATTR, the mutated TTR breaks apart into single units that misfold, clump together, and form stiff fibers called amyloid deposits.
These amyloid fibers build up in tissues throughout the body, particularly around peripheral nerves and the heart. Over time, the deposits cause progressive nerve damage that leads to pain, numbness, weakness in the hands and feet, and eventually problems with digestion, blood pressure regulation, and cardiac function. The disease is relentless because the liver keeps producing the faulty protein, which means new amyloid deposits form continuously.
RNA Interference: The Core Mechanism
Onpattro stops the problem at its source by preventing liver cells from making TTR protein in the first place. It does this through RNA interference, a natural biological process that cells already use to regulate their own gene activity. Here’s how it works step by step.
Your cells build proteins by first copying a gene’s instructions into a messenger molecule called mRNA. That mRNA then travels to the cell’s protein-making machinery, which reads the instructions and assembles the protein. Onpattro contains a tiny synthetic strand of genetic material (called small interfering RNA, or siRNA) that is designed to match a specific section of the TTR mRNA. When the siRNA finds its target, it latches on and flags the mRNA for destruction. The cell’s own enzymes then chop up the mRNA before it can be read, so the TTR protein never gets made.
The siRNA in Onpattro targets a region of the TTR gene that is shared across both the normal and mutated versions of the protein. This means it reduces total TTR production, eliminating the raw material that would otherwise misfold and form amyloid deposits.
How the Drug Reaches the Liver
Getting a fragile strand of synthetic RNA into liver cells is one of the biggest engineering challenges in this type of therapy. Naked RNA injected into the bloodstream would be torn apart by enzymes within minutes. Onpattro solves this by wrapping the siRNA inside lipid nanoparticles, essentially tiny fat-based capsules that serve two purposes: they shield the RNA from being degraded in the blood, and they guide it into liver cells.
The lipid nanoparticles are designed to attract a blood protein that normally shuttles cholesterol into the liver via LDL receptors. Liver cells readily take up these particles the same way they absorb cholesterol. Once inside the cell, the nanoparticle encounters an acidic environment that causes it to break open and release the siRNA, which then finds and silences the TTR mRNA.
What Happens During Treatment
Onpattro is given as an intravenous infusion once every three weeks. At least 60 minutes before each infusion, you receive a set of premedications to reduce the chance of an infusion-related reaction. These include a corticosteroid, acetaminophen, and two types of antihistamines. The premedications are a standard part of every session.
Because Onpattro dramatically reduces TTR protein levels, and TTR is one of the body’s main carriers of vitamin A, treatment causes vitamin A levels in the blood to drop. To offset this, patients take a daily oral vitamin A supplement of approximately 2,500 IU throughout the course of therapy. Without supplementation, prolonged vitamin A deficiency could lead to eye problems. Vitamin A levels are typically checked before treatment begins, and any existing deficiency needs to be corrected first.
How Effective the Treatment Is
The landmark clinical trial for Onpattro, called APOLLO, tested the drug in 225 people with hATTR polyneuropathy over 18 months. Researchers measured nerve function using a composite score that captures muscle weakness, reflexes, and sensory ability. Patients on placebo worsened by an average of 28 points on this scale, reflecting the steady nerve damage the disease causes when untreated. Patients receiving Onpattro, by contrast, actually improved by an average of 6 points. That’s a 34-point difference between the two groups, a result that was statistically significant.
This was a striking finding because hATTR polyneuropathy is a progressive disease. Simply slowing the decline would have been considered a success. The fact that Onpattro reversed some of the nerve impairment suggested that reducing TTR production gives the body a chance to clear existing amyloid deposits and partially recover nerve function. The benefits extended beyond nerve scores to quality-of-life measures, walking ability, and nutritional status.
Why Reducing the Protein Matters
The therapeutic logic behind Onpattro is straightforward: if you stop making the protein that misfolds, you cut off the supply of new amyloid. With less TTR circulating in the blood, fewer molecules are available to break apart, aggregate, and deposit in tissues. Over time, the body can begin to clear some of the existing amyloid burden, which is likely why patients in the APOLLO trial saw modest improvements rather than just stabilization.
This approach differs fundamentally from older treatments like liver transplantation, which replaces the organ producing the mutant protein, or stabilizer drugs, which try to hold the TTR structure together so it doesn’t fall apart. Onpattro operates upstream of both strategies by preventing the protein from being produced at all. It targets both the mutant and normal versions of TTR, but clinical evidence shows the net benefit of reducing amyloid formation far outweighs the loss of normal TTR function, provided vitamin A is supplemented.
Who Onpattro Is For
Onpattro is approved specifically for adults with polyneuropathy caused by hereditary transthyretin amyloidosis. This means the primary qualifying symptom is nerve damage, including numbness, tingling, pain, or weakness in the extremities, confirmed to be caused by a TTR gene mutation. The diagnosis typically involves genetic testing to identify the mutation and a biopsy or imaging to confirm amyloid deposits. Many patients also have cardiac involvement, and while Onpattro is not separately approved for the heart-only form of the disease, the reduction in TTR protein can benefit cardiac amyloid burden as well.