tafamidis and Amyloidosis--Familial

tafamidis has been researched along with Amyloidosis--Familial* in 2 studies

Other Studies

2 other study(ies) available for tafamidis and Amyloidosis--Familial

ArticleYear
Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients.
    Science translational medicine, 2017, Sep-13, Volume: 9, Issue:407

    Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.

    Topics: Amyloidosis, Familial; Benzoxazoles; Case-Control Studies; Cross-Linking Reagents; Diazomethane; Genotype; Humans; Ions; Light; Molecular Probes; Molecular Weight; Peptides; Prealbumin; Protein Folding; Protein Multimerization; Protein Structure, Secondary; Proteolysis; Proteomics; Solubility

2017
Quantification of quaternary structure stability in aggregation-prone proteins under physiological conditions: the transthyretin case.
    Biochemistry, 2014, Oct-21, Volume: 53, Issue:41

    The quaternary structure stability of proteins is typically studied under conditions that accelerate their aggregation/unfolding processes on convenient laboratory time scales. Such conditions include high temperature or pressure, chaotrope-mediated unfolding, or low or high pH. These approaches have the limitation of being nonphysiological and that the concentration of the protein in solution is changing as the reactions proceed. We describe a methodology to define the quaternary structure stability of the amyloidogenic homotetrameric protein transthyretin (TTR) under physiological conditions. This methodology expands from a described approach based on the measurement of the rate of subunit exchange of TTR with a tandem flag-tagged (FT₂) TTR counterpart. We demonstrate that subunit exchange of TTR with FT₂·TTR can be analyzed and quantified using a semi-native polyacrylamide gel electrophoresis technique. In addition, we biophysically characterized two FT₂·TTR variants derived from wild-type and the amyloidogenic variant Val122Ile TTR, both of which are associated with cardiac amyloid deposition late in life. The FT₂·TTR variants have similar amyloidogenic potential and similar thermodynamic and kinetic stabilities compared to those of their nontagged counterparts. We utilized the methodology to study the potential of the small molecule SOM0226, a repurposed drug under clinical development for the prevention and treatment of the TTR amyloidoses, to stabilize TTR. The results enabled us to characterize the binding energetics of SOM0226 to TTR. The described technique is well-suited to study the quaternary structure of other human aggregation-prone proteins under physiological conditions.

    Topics: Amino Acid Substitution; Amyloid; Amyloidosis, Familial; Benzophenones; Benzoxazoles; Binding Sites; Drugs, Investigational; Fluorescent Dyes; Humans; Kinetics; Models, Molecular; Mutant Proteins; Nitrophenols; Nootropic Agents; Prealbumin; Protein Aggregation, Pathological; Protein Stability; Protein Structure, Quaternary; Protein Unfolding; Recombinant Proteins; Thermodynamics; Tolcapone

2014