Towards Therapies Targeting the Mechanisms of Transthyretin Amyloidosis

There are twenty or so different proteins in the human body that can form amyloids, a misfolding of the protein that can encourage other molecules of the same protein to misfold in the same way. These misfolded proteins join together to form solid deposits - amyloids - that are associated with a complex, problematic biochemistry that disrupts cell and tissue function. Once underway in earnest, this formation of amyloids and the resulting pathology is known as amyloidosis.

Transthyretin is one of the proteins capable of forming amyloid, and transthyretin amyloidosis is found to some degree in every older individual. Most past research has focused on genetic mutations that cause severe and early transthyretin amyloidosis, but in recently years evidence has accumulated to suggest that this form of amyloid makes a meaningful contribution to the development and progression of cardiovascular disease - and a range of other age-related conditions - in all older people.

The biochemistry of transthyretin amyloid formation lends itself to disruption in a number of different ways, most of which can be applied to either mutant or normal transthyretin. A few companies have developed or are in the process of developing small molecule drugs to inhibit amyloid formation in order to allow clearance mechanisms, such as ingestion of amyloid by immune cells, to catch up. Others, such as Covalent Bioscience target the removal of amyloid without seeking to interfere in its creation; periodic treatments would keep amyloid levels low. This latter approach to producing therapies to treat age-related conditions is less well supported than I would like. There are any number of forms of metabolic waste that could be cleared to remove their impact on aging.

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Transthyretin (TTR) amyloidoses are under-recognized systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis

The hallmark of ATTR amyloidosis is the extracellular deposition of aggregated TTR or TTR fibrils in tissues. The process of TTR aggregation and fibril formation is not completely elucidated, however biochemical and biophysical evidences indicate that the tetrameric form of TTR becomes unstable and the protein dissociates into dimers and monomers presenting a partially unfolded conformation which self-assemble into toxic non-fibrillar aggregates and, later into amyloid fibrils that accumulate as amyloid deposits throughout the body.

The mechanism by which the tetramer disassembles and aggregates into amyloid fibrils has been considered the main driver of the disease. However, TTR proteolysis, namely occurring in the cardiac tissue, as well as its modulation have been increasingly documented as fundamental for understanding the development and progression of ATTR amyloidosis.

Many therapeutic approaches have been suggested for the treatment of ATTR amyloidosis targeting different steps of the pathology. Those therapies include interventions from the synthesis of the TTR variants through liver transplant or gene silencing therapies and clearance of amyloid deposits. Additionally, several compounds have been suggested for the treatment of ATTR amyloidosis by targeting different steps of the amyloid formation. The main steps include TTR stabilization, inhibition of oligomerization, and fibril disruption.

Although some the available therapies are more efficient than others, it becomes increasingly evident that combination of different therapies may improve the therapeutic outcome. In this sense, it would be interesting to test TTR gene silencing therapies in combination with protein stabilizers or disruptors of pre-existing amyloid deposits.

Comments

The whole field is all talk no action.

Posted by: Tiny Mouse at February 10th, 2021 12:41 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.