A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction

Abstract

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Stress-responsive regulation of extracellular proteostasis

“…This increases the population of nonnative TTR in the extracellular environment, bypassing the rate-limiting tetramer dissociation step of TTR aggregation and accelerating aggregation into soluble TTR oligomers commonly associated with toxicity (Chen et al, 2016). This suggests that increased secretion of nontetrameric TTR from the liver-the primary site of TTR synthesis-could exacerbate protein aggregation in the blood and contribute to the increased population of nonnative TTR observed in plasma collected from TTR amyloid disease patients suffering from polyneuropathy (Schonhoft et al, 2017;Jiang et al, 2021). Similar results were observed in mouse models of TTR amyloid disease, where age-dependent deposition of TTR aggregates in the heart correlated with aberrant expression of proteostasis factors in the liver (Buxbaum et al, 2012).…”

Evidence From Human Placenta, Endoplasmic Reticulum–Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia

“…35,36 TTR oligomers are cytotoxic to cells in tissue culture. 35,36 TTR-derived fibril deposition has been associated with 3 systemic amyloid diseases, 2 associated with variant protein structures, that is, familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy, and 1 in which the protein structure is wild type, senile systemic amyloidosis. 35,36 Intracellular misfolded and aggregated proteins are removed by the UPR machinery and the autophagy-lysosomal degradation system, respectively.…”

“…The free monomers are aggregation prone, particularly if they carry a mutation or have undergone posttranslational oxidative change. 35,36 TTR oligomers are cytotoxic to cells in tissue culture. 35,36 TTR-derived fibril deposition has been associated with 3 systemic amyloid diseases, 2 associated with variant protein structures, that is, familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy, and 1 in which the protein structure is wild type, senile systemic amyloidosis.…”

Metabolomic fingerprinting for biomarker discovery in renal amyloidosis

“…Identification of potential biomarkers in biological fluids promotes better understanding of disease onset and progression [41]. Previous studies have showcased the role of biological markers in early diagnosis of amyloid-associated disorders [29,[42][43][44][45][46]. Despite of the presence of biological markers signifying renal failure and its associated diseases [47,48], distinct diagnostic markers for renal amyloidosis has not been explored till date.…”