Navigating the Data, Treatments and Breakthroughs of hATTR Amyloidosis

Cancer Cell in human showing abnormal cells.Medical science background concept.

ATTR amyloidosis means A for Amyloid and the TTR is short for the protein “transthyretin.” ATTR is one term that represents different kinds of mutations in a TTR gene that is inherited. That gene mutation makes the transthyretin unstable, so amyloid protein misfolding occurs. The amyloid fibrils then go out into the body and can damage nerves and/or organs, depending on the type of TTR mutation that the patient has inherited. TTR is mainly manufactured in the liver.

The majority of hereditary amyloidosis types are TTR-related, and there are many different variations within ATTR. Most ATTR diseases have a hereditary pattern of organ involvement, approximate age of onset and associated symptoms. It is common that symptoms do not appear until a person is an adult and the degree and severity of illness depends on the individual.

In the past, because ATTR often involves nerve or cardiac involvement, some terms were used when the chemical variations were less defined. Examples of these outdated terms include FAP (Familial Amyloid Polyneuropathy) and FAC (Familial Amyloid Cardiomyopathy).

Today, the different forms of ATTR are termed according to the “chemically based” name of the transthyretin protein variation. An example of this would be ATTRV30M (for ATTR Val30Met), which is the most common ATTR variation.

According to the Amyloidosis Foundation, today’s treatment plans are two-fold:

Supportive treatment – treating your symptoms and organ damage
Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.

Supportive Treatment
Supportive treatment is helpful for various symptoms, including peripheral neuropathy, autonomic neuropathy, and cardiac and kidney problems, and can change the quality of life for many people. There are several medications that can be prescribed to treat peripheral neuropathy, which can cause tingling or burning in some parts of the body. These medications can help with pain relief and nerve damage. If a patient has autonomic neuropathy, symptoms can vary, with common problems affecting blood pressure, heart rate, digestion, and perspiration, depending on the location of the damage to the nerves. Other gastrointestinal dysfunctions may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. Doctors can prescribe medications to help with these symptoms to lessen the pain and the symptom itself.

Management of heart problems, heart failure, and kidney dialysis (when needed) make a significant improvement on a patient’s quality of life. Reversing any damage to the organs and other parts of the body is difficult to achieve. If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.

Source Treatment
For most ATTR variations, the liver is the main source of amyloid production. However, the liver itself is not affected by the disease in most cases and the amyloid burden causes damage in other parts of the body. A liver transplant is very helpful in reducing (or stopping) the amyloid deposits. It can stabilize or improve neurological symptoms as well as gastrointestinal problems (which can correct poor nutrition and overall health). However, the statistics vary as to who can benefit from these transplants, with the more common ATTR Val30Met having the highest success rate. The outcome of liver transplantation is largely dependent on the mutation that exists in the patient. In some cases, amyloid deposition does completely stop after transplantation, so research is ongoing in this area. For those patients with cardiac symptoms, studies have shown that heart problems may continue after a liver transplant. In some situations, a combined heart and liver transplant will help a patient with an ATTR variant that produces advanced cardiac problems. In 2018, two drugs were approved by the FDA for ATTR polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The first was ONPATTRO (patisiran) lipid complex injection, a first of its kind RNA interference therapeutic. This drug aims to silencing the gene expression.