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

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 circulatin...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 9; pp. 1 - 8
Main Authors Jiang, Xin, Labaudinière, Richard, Buxbaum, Joel N., Monteiro, Cecília, Novais, Marta, Coelho, Teresa, Kelly, Jeffery W.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 02.03.2021
Subjects
Amyloid
Biological Sciences
Biomarkers
Degenerative diseases
Disease
Enzyme-linked immunosorbent assay
Fibrils
Monomers
Oligomers
Plasma levels
Plasmas (physics)
Polyneuropathy
Pretreatment
Reduction
Transthyretin
early diagnosis
biomarker
NNTTR
response to therapy
Online AccessGet full text

Cover

More Information
Summary: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 enzymelinked 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 diseasemodifying 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
Author contributions: X.J. and J.W.K. designed research; X.J., R.L., J.N.B., and C.M. performed research; M.N. and T.C. contributed new reagents/analytic tools; C.M., M.N., and T.C. performed clinical annotation of the majority of the samples used in this study; X.J., R.L., J.N.B., and C.M. analyzed data; and X.J., R.L., J.N.B., and J.W.K. wrote the paper.
Competing interest statement: R.L. and J.W.K. receive royalties related to tafamidis sales and sales milestones. T.C. has received funding from Pfizer Inc., Alnylam Pharmaceuticals, and Ionis Pharmaceuticals for scientific meeting expenses (travel, accommodation, and registration), and has received honoraria from Pfizer Inc. and Alnylam Pharmaceuticals for training. Protego Biopharma has filed a patent application (US20160039916A1) to cover the antibodies/use associated with the assay.
Edited by Susan Marqusee, University of California, Berkeley, CA, and approved December 17, 2020 (received for review July 29, 2020)
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2016072118