Evidence map›Paper›PMID 27122057›Full record

ArticleScientific reports2016

Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.

Natalie J Galant, Antoinette Bugyei-Twum, Rishi Rakhit, Patrick Walsh, Simon Sharpe, Pharhad Eli Arslan, Per Westermark, Jeffrey N Higaki, Ronald Torres, José Tapia and 1 more

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed.

  1. Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?Clinical research in cardiology : official journal of the German Cardiac Society · 2026
    Review
  2. Review
  3. Conformational inhibitors of protein aggregation.Current opinion in structural biology · 2023
    Review
  4. Review
  5. Review
  6. Review
  7. Review
  8. Review
  9. Review
  10. Advances in the Treatment of Cardiac Amyloidosis.Current treatment options in oncology · 2020
    Review
  11. Modulation of the Mechanisms Driving Transthyretin Amyloidosis.Frontiers in molecular neuroscience · 2020
    Review
  12. Review
  13. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review.Journal of the American College of Cardiology · 2019
    Review
  14. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Natalie J GalantPrincess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Antoinette Bugyei-TwumPrincess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Rishi RakhitDepartment of Chemical and Systems Biology, Stanford University, CA 94305, USA.
Patrick WalshMolecular Structure and Function Program, the Hospital for Sick Children, Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Simon SharpeMolecular Structure and Function Program, the Hospital for Sick Children, Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Pharhad Eli ArslanPrincess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Per WestermarkDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Jeffrey N HigakiDepartments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
Ronald TorresDepartments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
José TapiaDepartments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
Avijit ChakrabarttyPrincess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.

Funding

CIHR
6 · The paper itself

Abstract

Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

Indexed as

Protein FoldingAmyloidosisAnimalsAntibodiesImmunotherapyPrealbuminProtein BindingRabbitsAntibodiesPrealbumin

Identifiers

PMID27122057
PMCPMC4848561

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.