Researchers have discovered that an existing drug can slow the progression of rare forms of transthyretin amyloidosis caused by mutation by interfering in the formation of this type of amyloid. It is unclear as to how useful this would be in practice for the age-related accumulation of transthyretin amyloid known as senile systemic amyloidosis that occurs in every individual, however, as that happens at a much slower pace over a greater span of time. The growing presence of this amyloid is implicated in a range of age-related conditions, particular cardiovascular disease. The ideal approach to amyloidosis, whether age-related or not, is clearance of amyloid rather than slowing its formation, however. Clearance can be applied at any point in the progression of the amyloidosis to obtain benefits, and applied repeated as needed, at a much lower cost. Slowing progression requires constant treatment at a much higher cost, and produces smaller and diminishing benefits. Fortunately a therapy capable of transthyretin amyloid has already been successful in a small trial, though the pace of clinical development in this field is, as ever, glacial.
Researchers have published the results of a drug repositioning study in which they describe a powerful drug, SOM0226 (tolcapone) that could significantly improve the pharmacological treatment of familial transthyretin amyloidosis (ATTR). ATTR is a rare degenerative disease that mainly affects the nervous system and heart muscle tissue (myocardium), and which is usually passed on from parents to children. It originates when the liver and other areas of the organism produce mutations of the protein transthyretin (TTR), which lose their functional structure. This causes toxic aggregates of amyloid fibres to build up, which, depending on the mutation involved, are deposited in different organs, such as the brain, the kidneys, the nerves, the eyes, or the myocardium, causing them to malfunction and bringing on the various forms of the disease. To prevent the disease from progressing, a liver transplant or liver and heart transplant is needed.
The researchers conducted trials in vitro in cell cultures and ex vivo in human plasma and in mouse models of the disease to show that tolcapone is a powerful inhibitor of the aggregation of amyloid fibres by TTR. Tolcapone acts by imitating the process by which the thyroid hormone - T4 or thyroxine - binds to TTR in the bloodstream. Just like the hormone, the drug binds closely to the protein, tying together the four protein sub-units that form the protein's structure. This binding has been proven to stabilise the protein, preventing the sub-units from separating and then forming aggregates. This is a hitherto unknown property of the drug, which is used to treat Parkinson's disease. The compound turns out to be four times more effective than the only medicine currently available for treating the polyneuropathic variant of ATTR. The results were positive for all variants of the disease that were studied: familial amyloid polyneuropathy and cardiomyopathy (which affects the peripheral nerves and the myocardium, respectively) and senile systemic amyloidosis, a sporadic form that appears in a very high percentage of men over 60 years of age (and also affects the myocardium). In addition, the treatment was shown to cross the blood-brain barrier, making it the first to tackle the variants that affect the central nervous system.
According to the researchers, this molecule has the potential to become an effective drug for preventing the protein depositions that cause the disease and slowing down its progress, one that could be on the market within five years, as it has already been tested in a clinical trial with persons affected by the neuropathic variant.