Evolving landscape in the management of transthyretin amyloidosis

Abstract

Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTRRx, an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease.

Transthyretin Cardiac Amyloidosis in Older Americans

“…Revusiran results in >80% knock down of circulating TTR. [54] Revusiran, delivered via subcutaneous injection, was being evaluated in patients with ATTRm but not ATTRwt cardiac amyloidosis in a phase III trial called ENDEAVOUR and in a phase II trial that included both ATTRm and ATTRwt subjects. The sponsor recently halted development of revusiran because of new onset or worsening peripheral neuropathy in the phase II trial and because of an imbalance in mortality between revusiran and placebo in the phase III trial, ENDEAVOUR.…”

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…This protein is a common study subject in amyloidogenesis research due to its susceptibility to conformational changes which produce fibrillary structures, both in vivo and in vitro [25][26][27][28][29].…”

“…Our second study subject is human transthyretin, in which the distribution of hydrophobicity density diverges from theoretical expectations (based on the FOD model). This protein exhibits a notable tendency to generate amyloid fibrils, both in vitro and in vivo [24][25][26][27][28][29].…”

V122I TTR Cardiac Amyloidosis in Patients of African Descent

“…Recognition of the presence of amyloid cardiomyopathy is particularly important now because, as described by the authors, several promising potential treatments for both wild-type and mutant ATTR are currently being actively investigated. 10 These therapies may soon change the course of this disease in the same way that chemotherapy has extended the life of patients with AL amyloidosis. In addition, by raising the question of the curious paucity of patients with typical V122I cardiac amyloidosis, it brings to mind the Sherlock Holmes story, in which the failure of the dog to bark led to a solution of an otherwise seemingly insoluble murder.…”