An Overview of the Mechanisms of Transthyretin Amyloidosis

A score or so different types of amyloid can form in the human body, each a protein that can become altered or misfolded in a way that encourages other molecules of the same protein to also alter or misfold. These broken proteins aggregate together into sheets and fibrils, forming solid deposits in and around cells that interfere with the normal function of tissues, or are actively toxic. Transthyretin is one such protein, and transthyretin amyloidosis is present to some degree in all older people. Evidence of recent years suggests that it is a factor in 10% of heart failure cases in old people in general, and it may be the dominant cause of cardiac mortality in supercentenarians, those aged 110 or older.

The open access paper noted here is an interesting overview of the mechanisms by which amyloidosis occurs in the case of transthyretin, in the context of trying to predict who is most at risk and should therefore be treated. Eidos Therapeutics has a treatment in the late stage of development that interfers enough with the mechanisms of transthyretin aggregation to be worth the effort, though as for most such lines of development it will initially be targeted at cases in which transthyretin is mutated in ways that accelerate amyloidosis, rather than as a preventative therapy for the entire population. More aggressive degradation of amyloid will likely be needed, such as via the use of catabodies, a line of work at an earlier stage of development at Covalent Bioscience, but nonetheless promising.

Proposing a minimal set of metrics and methods to predict probabilities of amyloidosis disease and onset age in individuals

The rate of synthesis of transthyretin (TTR) is constant. For proteostasis, the rate of removal of TTR must equal the rate of synthesis. TTR in plasma is largely in the tetrameric form, (TTR)4, but dissociates to give very low, but significant concentrations of dimers and monomers. Removal of TTR from plasma proceeds via monomers.

Monomers undergo two processes that remove them from solution, proteolysis or aggregation. The combined rates of these two pathways equals the total rate of monomer removal, which is also equal to the rate of production of monomer via dissociation of tetramer. Depending on the relative rates, either of the two reaction pathways could account for anywhere from 100% to 0% of the rate of monomer removal. The critical monomer concentration for aggregation is unknown, however the cause of aggregation develops slowly over time. Once amyloidosis begins, the rate of development of amyloidosis is determined by the rate of monomer incorporation into various aggregates that lead to fibrils and amyloids.

Destabilizing tetramer by pleiotropic mutations leads to greater dissociation of monomer and a higher, variant-dependent concentration of TTR monomer in plasma. Mutations are not required for TTR amyloidosis formation; point mutations only modify the equilibrium concentrations. Amyloidosis caused by wild-type TTR follows the same mechanism as amyloidosis caused by variants of TTR and thus should be considered as variants of the same disease for purposes of clinical studies.

Amyloidosis begins when the rate of TTR proteolysis decreases relative to the rate of amyloid formation and monomer concentration increases sufficiently to allow significant oligomerization into fibrils and amyloids. The cause of a decrease in the rate of proteolysis of TTR remains to be identified. When the tetramer is stabilized by drugs or stabilizing mutations, the concentration of tetramer will increase in plasma to a steady-state level determined by the rate of proteolysis.

Comments

It might be of interest to note that the FDA has already approved a drug for TTR.

https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vyndaqel_and_vyndamax_for_use_in_patients_with_transthyretin_amyloid_cardiomyopathy_a_rare_and_fatal_disease

> Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal condition that is caused by destabilization of a transport protein called transthyretin, which is composed of four identical sub units (a tetramer). When unstable transthyretin tetramers dissociate, they result in misfolded proteins that aggregate into amyloid fibrils and deposit in the heart, causing the heart muscle to become stiff, eventually resulting in heart failure. There are two sub-types of ATTR-CM: hereditary, also known as variant, which is caused by a mutation in the transthyretin gene and can occur in people as early as their 50s and 60s; or with no mutation and associated with aging, known as the wild-type form, which is thought to be more common and usually affects men after age 60.

Posted by: John at November 27th, 2020 6:55 PM

Sadly there has not been any news out of Covalent for years it seems, I hope they haven't run out of funding. Perhaps they are now caught in the valley of death between promising lab results and having enough money to build the animal models necessary to convince the FDA to allow a stage 1 trial, as well as enough money to run the trial?

Posted by: jimofoz at November 28th, 2020 8:27 AM

Curcumin and epigallocatechin gallate (EGCG; active ingredient in green tea) have both been hypothesized to protect against transthyretin (TTR) amyloidosis. As they both have good safety records in low dosages, they could possibly be used as a precautionary measure awaiting better solution. This may be particularly relevant for individuals carrying mutations that further destabilize TTR, such as Val30Met.

The evidence for these natural remedies isn't very convincing, though. The following study found that both modulate TTR amyloidogenicity in vitro and showed that EGCG supplementation inhbitit amyloid deposits in mice models:

https://www.tandfonline.com/doi/full/10.3109/13506129.2012.668502

EGCG has been the subject of a few clinical studies, with mixed results. Curcumin apperas not to have been studied clinically in this context, but here is a recent review of preclinical research:

https://www.mdpi.com/1422-0067/20/6/1287

On a slightly different note, recent research has suggested that mitochondria may play an important role in inheritable familial amyloid neuropathy (FAP) and possibly explain differences in penetrance and onset among endemic areas. The following study found that mtDNA copy numbers may be more than twice as high in Val30Met carries and higher in symptomatic carriers than asymptomatic carriers. They suggest excessive ROS production as an explanation:

https://jnnp.bmj.com/content/jnnp/89/3/300.full.pdf

In light of these findings, it would be interesting to explore if mitochondrially targeted antioxidants such as MitoQ would be helpful in preventing protein misfolding, e.g. using the FAP mouse models in the previous studies. To my knowledge, this question has not been considered.

Posted by: Slumpvandraren at November 30th, 2020 5:56 AM

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