Treatment of all types of amyloidosis is currently based on the following principles:
- Reducing the supply of amyloid forming precursor proteins.
- Supporting the function of organs containing amyloid.
When amyloid precursor protein supply is controlled:
- existing amyloid deposits often regress (become smaller)
- new amyloid deposits stop appearing
- organ function is often preserved and may also recover
Reducing variant TTR supply
Genetic based therapies
Two recently developed genetic therapies, patisiran and inotersen, aim to ‘switch off’ the TTR gene in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Patisiran belongs to the small interfering RNA drug class and inotersen belongs to the antisense oligonucleotide drug class. In clinical trials in patients with hereditary ATTR amyloidosis both these drugs improved neuropathy symptoms, quality of life, daily activities and disability.
Patisiran and inotersen have been approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for treating neuropathy caused by hereditary ATTR amyloidosis.
On 22 May 2019 NICE published guidance recommending inotersen for treating stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis.
On 14 August 2019 NICE published guidance recommending patisiran for treating hereditary transthyretin amyloidosis in adults with stage 1 and stage 2 polyneuropathy.
Both inotersen and patisiran have now been approved by NHS England for this indication.
So far trials have only assessed the impact of these drugs on nerve damage caused by ATTR amyloidosis. Effects on cardiac ATTR amyloidosis have not been formally assessed and patients with wild-type ATTR amyloidosis were not included in the drug trials.
The National Amyloidosis Centre can now offer patients with ATTR amyloidosis, subject to various eligibility criteria demanded by the pharmaceutical companies, various opportunities for treatment with the new drugs or for participation in clinical trials. For details of ongoing trials at the NAC see here.
Liver transplantation may be helpful for some patients with hereditary ATTR amyloidosis, mainly for patients with the Val30Met mutation. Liver transplantation is not a treatment for wild type ATTR amyloidosis.
All the TTR in the blood, which forms the amyloid deposits everywhere except in the eye and the blood vessels around the brain, is made in the liver. Liver transplantation is therefore a treatment option for some patients with hereditary ATTR amyloidosis. The liver which forms the abnormal, ‘variant’ TTR is removed and replaced by a donor liver making normal, ‘wild type’ TTR. The aim is to prevent the formation of further amyloid deposits by reducing the supply of the amyloidogenic precursor TTR.
Liver transplantation has been performed in hundreds of patients with hereditary ATTR amyloidosis around the world. In many cases this has been successful, leading to stabilisation of disease. Success is greatest when transplantation is performed:
- early in the course of disease before there has been too much damage to the nerves or the heart
- in younger patients in patients with the TTR Val30Met mutation
Unfortunately, in some patients amyloid deposits in the heart have continued to progress even after transplantation. It seems that the abnormal TTR fibrils which formed amyloid deposits before the liver transplantation act as a template encouraging deposition of normal TTR as amyloid. Thus the normal TTR protein (wild type TTR) produced by the new liver builds up on top of the existing amyloid deposits containing the abnormal TTR. This problem has appeared most often in older patients with mutations other than Val30Met.
For hereditary ATTR amyloidosis, combined heart and liver transplant has been performed in a few dozen cases around the world. This operation is only an option for a minority of patients, and it carries significant risks.
Most patients with wild type ATTR amyloidosis are too elderly to undergo a heart transplant. The risk of complications from this major operation is high with advanced age. But heart transplantation may be an option for younger, otherwise healthy patients with this condition. The 2 patients who presented to the NAC before age 60 with wild type ATTR amyloidosis survived 10 and 20 years after heart transplantation.
Supporting amyloidotic organ function
In all types of amyloidosis it is important that treatment should support the function of organs containing amyloid. In ATTR amyloidosis this may include: