ATTR cardiomyopathy: gene silencers and gene stabilizers

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a disorder that causes protein deposits to accumulate in the heart muscle, affecting the heart’s ability to pump blood and potentially leading to heart failure. ATTR-CM is a rare condition, though exact numbers on how many people are affected by this disease are not known.

Gene silencers and gene stabilizers are two potential treatment options for ATTR-CM. Below is an overview of how these therapies work.

How does ATTR-CM affect the heart?

To understand how ATTR-CM is treated, it helps to take a closer look at what is happening in the body when a person has ATTR-CM.

• Transthyretin (TTR) refers to a protein called transthyretin, which transports vitamins and hormones to different areas of the body. When a person has a form of TTR amyloidosis, the body makes abnormal (misfolded) TTR proteins, which clump together and form deposits.
• Amyloids are deposits of proteins. Some amyloids are functional and beneficial to the body. Others, like the TTR amyloids that occur with ATTR-CM, are harmful to the body and disrupt the function of organs and tissues.
• Cardiomyopathy refers to diseases that affect the heart muscle. In ATTR-CM, amyloid deposits accumulate in the heart muscle, causing the muscle to become stiff and rigid and less effective at pumping blood.

Can other parts of the body be affected?

In addition to accumulating in the heart muscle, TTR amyloids can also accumulate in the nervous system. Symptoms will depend on what part of the nervous system is affected. Pain, tingling, and numbness in the hands and feet are common. This can also affect the parts of the nervous system that control bodily functions like digestion, urination, and blood pressure. TTR amyloids can also accumulate inside and damage the kidneys.

Is ATTR-CM a genetic disorder?

In some cases, ATTR-CM is caused by a genetic variation or mutation that is inherited from a person’s biological parents. This type is known as hereditary ATTR-CM (hATTR-CM).

In other cases, ATTR-CM occurs without an inherited genetic variation or mutation. Instead, normal TTR proteins become unstable, lose structure, and form amyloids. This type is known as wild type ATTR-CM (wATTR-CM). Advancing age is a risk factor for wild type, with most cases occurring in males over the age of 70. Wild type is more common than hereditary ATTR-CM.

What are gene stabilizers and gene silencers?

Knowing that ATTR-CM is caused by misfolded proteins, medical researchers have looked for ways to target the misfolded proteins and prevent TTR amyloids from accumulating inside cardiac muscle. This has led to the development of gene stabilizers and gene silencers that treat ATTR-CM. While these treatments have similar names, they work in different ways.

What is a gene silencer?

Gene silencers are drugs that block specific genes from working. In the treatment of ATTR-CM, TTR silencers target the TTR gene, a section of DNA that contains instructions for making TTR proteins. This reduces the amount of TTR proteins being produced, which will reduce the amount of TTR proteins that misfold and become amyloids.

What is a gene stabilizer?

Gene stabilizers are drugs that attach to TTR proteins to help the proteins maintain structural integrity, avoid misfolding, and prevent the formation of amyloids.

What other treatments are used?

Treatment may also include supportive therapies to help with specific problems caused by ATTR-CM, such as therapies to improve heart function, treat irregular heart rhythm (arrythmia), or treatments for neurological problems (if ATTR has also affected the nervous system). New treatments for ATTR-CM are also under development.

Because of the complex nature of this condition, and the fact that it is uncommon, it’s important to work with a healthcare team that is experienced in treating ATTR-CM.

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