Nearly 50,000 people are affected by hATTR amyloidosis. Hereditary ATTR or hATTR amyloidosis is a family condition; it is known to be autosomal dominant. This means a person has a high probability of developing this condition with only one copy of the affected gene inherited from one parent.
What are the causes of hATTR amyloidosis?
Amyloidosis is caused when amyloid fibrils, an abnormal protein starts to build up in the tissues and organs. The shape of the affected organs and tissues changes. The way these organs and tissues work also changes.
There are six known types of amyloidosis, among which is hereditary ATTR or hATTR amyloidosis. hATTR is caused due to a mutation of a gene that affects the functioning of the transthyretin (TTR), a protein in the blood. TTR naturally occurs in the liver. It carries nutrients and vitamins such as vitamin A. When gene mutation occurs, the TTR protein misfolds; its shape becomes abnormal. The abnormal shape causes the protein to build up and deposit in the gastrointestinal, cardiac, and nervous systems. These protein deposits cause the symptoms of the condition. This is a permanent effect. So, most hATTR amyloidosis treatments are geared towards controlling the buildup of the protein.
hATTR amyloidosis treatments work towards alleviating the symptoms of the condition. The symptoms are never the same for two people even with the same mutation or within the same families. The initial symptoms start appearing between the mid-20s and mid-60s of a person. The symptoms will vary based on the part of the body affected.
- Peripheral nervous system: Symptoms include numbness, tingling, carpal tunnel syndrome, burning pain, loss of sensitivity to temperature, and weakness.
- Cardiac system: Symptoms include increasing fatigue, dizziness, shortness of breath, leg swelling, chest pain, palpitations, and abnormal heart rhythms.
- Autonomic dysfunction: Symptoms include urinary tract infection, excessive sweating, dizziness upon standing, sexual dysfunction, nausea, vomiting, diarrhea, severe constipation, and unintentional weight loss.
Other symptoms of hATTR amyloidosis are glaucoma, blurred or spotty vision, detached retina, progressive dementia, headache, seizures, weakness, kidney dysfunction, stroke-like episodes, loss of movement control, and abnormalities of the blood vessels or pupil on the white of the eye.
What are the treatment options?
There are a number of current and emerging hATTR amyloidosis treatments and therapies. Recently, two medicines for the condition were approved by the FDA. Although there is no permanent cure for the condition, the treatments, medications, and therapies help to lower the amount of TTR protein produced in the body. The treatments also help to manage the symptoms.
- Orthotopic liver transplant or OLT: One of the treatment options is orthotopic liver transplant or OLT. This treatment is usually done in the early stages of the condition. A patient has to meet multiple eligibility criteria to undergo OLT. Since most of the TTR protein is produced in the liver, it is expected that replacing the major source of the protein with a transplanted liver will slow down or even halt the progress of the condition. However, OLT is not effective in every case. In some cases, the new TTR protein produced by the transplanted liver accumulates on the preexisting deposits. Also, this treatment has other limitations including the limited availability of organs, surgical morbidity, and mortality along with the need for lifelong immunosuppression medicines and high cost of a liver transplant.
- FDA-approved medications: In 2018, two medicines undergoing clinical trials were approved by the FDA for hereditary ATTR amyloidosis. These are patisaran or OnpattroTM and inotersen or TegsediTM. These two are for those with symptoms of the peripheral nervous system. In May 2019, the FDA approved a third medication called tafamidis or VyndaqelTM. This medication has shown success in patients with cardiac system symptoms. Although the target groups are different for the medications, their effectiveness is based on the same principle. These medications work towards reversing or arresting the progression of heart failure that is generally associated with hATTR amyloidosis. Although approved by the FDA, these medications have not gone under production yet. Their pricing is still under discussion between pharmaceutical companies and insurers.
- Emerging therapies for hATTR amyloidosis treatment: There are three categories of emerging therapies that are undergoing research and clinical trials. The first category of therapies works by suppressing the production of TTR protein that caused hATTR amyloidosis. There are two RNA-based therapies undergoing evaluation in phase 3 clinical trials. These therapies are the antisense oligonucleotides (ASO) approach and the RNA interference (RNAi). The goal of these approaches is to lower the production of TTR protein. These work similar to OLT treatment. The second category of emerging therapies is based on the development of TTR stabilizers. Right now existing only in theory, the proposed stabilizers are expected to slow down the progression of amyloid production. This occurs by preventing the dissociation, misfolding, and misassembly of the mutated TTR protein.
The third category is immunotherapy. Using monoclonal antibodies, a regulated immune response is produced. The antibodies clear the protein deposits and control the symptoms of hATTR amyloidosis. Immunotherapy is currently undergoing multiple clinical trials.