RNA (Gene) Silencers

Living with ATTR amyloidosis means your body makes an unstable protein. This protein is called transthyretin, or TTR. This unstable TTR protein misfolds. It builds up in the body as clumps called amyloid. These clumps damage nerves and the heart. This damage causes the symptoms of ATTR amyloidosis.¹

New treatments can help stop this damage. One group of treatments is called RNA silencers, or gene silencers. These drugs work in a new way to stop the body from making the problem protein.^1,2

How do RNA silencers work?

Your body uses instructions in your genes to build proteins. Think of a gene like a blueprint in your DNA. To build a protein, the cell makes a copy of the blueprint. This copy is called messenger RNA, or mRNA. The cell uses this mRNA copy to build the TTR protein.^1-3

In people with ATTR amyloidosis, the TTR protein is unstable. The liver makes almost all of this unstable TTR protein. RNA silencers are drugs that stop this process. They "silence" the mRNA instructions for TTR.^1-3

These drugs find the TTR mRNA in the liver. They attach to the mRNA and cause it to break down. When the mRNA instruction copy is gone, the cell cannot build the TTR protein. This greatly lowers the amount of TTR protein in the blood. Less TTR protein means less amyloid buildup. This can help slow or stop the nerve damage caused by the disease.^1-3

Examples of RNA silencers

There are 4 RNA silencer drugs approved by the US Food and Drug Administration (FDA). Each NRA silencer works in a slightly different way. Which drug you are prescribed depends on the type of ATTR amyloidosis you have:^1,4-7

• Onpattro® (patisiran) – This drug uses RNA interference to degrade TTR mRNA and halt protein production in the liver. It is given intravenously (into a vein) every 3 weeks and is approved for hereditary ATTR (hATTR) polyneuropathy.
• Amvuttra® (vutrisiran) – This drug reduces TTR protein levels and is administered subcutaneously (just under the skin) every 3 months. It is approved for both hATTR polyneuropathy and ATTR cardiomyopathy in adults.
• Tegsedi™ (inotersen) – This drug is an antisense oligonucleotide (ASO). It binds to and degrades TTR mRNA, reducing protein synthesis. It is given as a weekly subcutaneous injection and is approved for hATTR polyneuropathy.
• Wainua® (eplontersen) – Also an ASO, eplontersen degrades TTR mRNA to reduce protein production. It is given as a monthly subcutaneous injection and is approved for hATTR polyneuropathy.

What are the possible side effects?

Side effects can vary depending on the specific drug you are taking.

A common side effect for all 4 of these drugs is a drop in vitamin A levels. Your body needs the TTR protein to move vitamin A. When these drugs lower your TTR protein, your vitamin A levels also go down. Your doctor will tell you to take a vitamin A supplement every day. Do not take more vitamin A than your doctor recommends.³

Other common side effects depend on the drug:^4-7

• Onpattro (patisiran) – The most common side effects are infusion-related reactions. These can include flushing, nausea, or headache during the infusion. Your doctor may give you other medicines before the infusion to help prevent this.
• Amvuttra (vutrisiran) – Common side effects include pain at the injection site, joint pain, and shortness of breath.
• Tegsedi (inotersen) – This drug has a boxed warning. This is the strictest warning from the FDA. It has this warning because it can cause a serious drop in blood platelets (thrombocytopenia) and serious kidney problems (glomerulonephritis). Because of these risks, you must have regular blood and urine tests before and during treatment. Other side effects include nausea, headache, and injection site reactions.
• Wainua (eplontersen) – Common side effects include injection site reactions and vomiting. This drug can also lower platelets and affect the kidneys, so you may need regular monitoring tests.

These are not all the possible side effects of RNA silencers. Talk to your doctor about what to expect when taking one of these drugs. You should also call your doctor if you have any changes that concern you when taking the drug.

Other things to know

Because some of these drugs carry serious risks, they may only be available through special programs. For example, Tegsedi requires enrollment in a monitoring program. Your healthcare team will discuss all of these requirements with you.^4-7

Before beginning treatment for ATTR amyloidosis, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you take. This includes over-the-counter drugs.