tolcapone and Amyloid-Neuropathies--Familial

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

Topics: Aging; Alkylating Agents; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Antibodies, Monoclonal; Benzoates; Benzoxazoles; Bridged Bicyclo Compounds, Heterocyclic; Cardiomyopathies; Catechol O-Methyltransferase Inhibitors; Heart Transplantation; Humans; Immunomodulating Agents; Oligonucleotides; Proteasome Inhibitors; Protein Folding; Pyrazoles; RNA, Small Interfering; Stem Cell Transplantation; Sulfonamides; Tolcapone

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Catechol O-Methyltransferase Inhibitors; Female; Humans; Male; Middle Aged; Mutation, Missense; Prealbumin; Proof of Concept Study; Protein Aggregation, Pathological; Tolcapone

The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.

Topics: Amyloid Neuropathies, Familial; Animals; Mice; Molecular Dynamics Simulation; Prealbumin; Tolcapone

To investigate the effect of tolcapone on cerebrospinal fluid (CSF) transthyretin (TTR) tetramer stability in patients with hereditary transthyretin (ATTRv) amyloidosis.. A total of 9 patients were enrolled in the study (3 men, 50.3 ± 14.4 years old). Three patients had central nervous system (CNS) involvement. Patients were assigned to receive tolcapone 300 mg/day or 600 mg/day for 7 days. Plasma and CSF were collected at baseline and 2 h after the final tolcapone dose.. The mean CSF tolcapone and 3-O-Methyltolcapone (3-OMT) concentration were 39.4 ± 36.3 ng/mL and 26.0 ± 4.9 ng/mL, respectively, after 7 days of tolcapone dosing. Tolcapone and 3-OMT were detected in the CSF of patients with or without CNS symptoms. The mean total study drug (tolcapone + 3-OMT) to TTR molar ratio in CSF was 1.15 ± 0.59. Orally administered tolcapone significantly increased CSF TTR concentration and decreased monomer content under semi-denaturing conditions. Eight adverse events (AEs) were reported in 6 patients. All AEs were mild in severity and resolved.. Tolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis.

Topics: Adult; Amyloid Neuropathies, Familial; Amyloidosis; Amyloidosis, Familial; Blood-Brain Barrier; Female; Humans; Male; Middle Aged; Prealbumin; Tolcapone

Transthyretin (TTR) is a causative protein of TTR amyloidosis (ATTR amyloidosis), a general term for diseases characterized by deposition of TTR amyloid fibrils in specific organs. ATTR amyloidosis can be ameliorated by stabilization of the TTR tetramer through the binding of small molecules. Here, we show that the clinical anthelmintic drugs bithionol (

Topics: Amyloid Neuropathies, Familial; Anthelmintics; Bithionol; Crystallography, X-Ray; Drug Repositioning; Humans; Prealbumin; Thermodynamics; Triclabendazole

Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis. DATABASES: PDB codes for A25T-TTR, V30G-TTR, and Y114C-TTR bound to tolcapone are 6TXV, 6TXW, and 6XTK, respectively.

Topics: Amyloid; Amyloid Neuropathies, Familial; Antiparkinson Agents; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Drug Repositioning; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Kinetics; Models, Molecular; Mutation; Neuroprotective Agents; Prealbumin; Protein Aggregates; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Denaturation; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Structure, Tertiary; Recombinant Proteins; Tolcapone; Urea

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation

Topics: Amyloid; Amyloid Neuropathies, Familial; Benzoates; Benzoxazoles; Cardiomyopathies; Diflunisal; Humans; Kinetics; Prealbumin; Protein Aggregates; Protein Binding; Protein Multimerization; Protein Subunits; Pyrazoles; Tolcapone

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases.

Topics: Administration, Oral; Amyloid Neuropathies, Familial; Animals; Benzoates; Biomimetics; Dogs; Entropy; Female; Humans; Male; Models, Molecular; Mutation; Prealbumin; Protein Conformation; Protein Stability; Pyrazoles; Serum Albumin, Human; Thermodynamics

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.

Topics: Administration, Oral; Amyloid Neuropathies, Familial; Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Cell Line; Dimerization; Drug Repositioning; Healthy Volunteers; Humans; Mice, Transgenic; Middle Aged; Nitrophenols; Prealbumin; Protein Aggregation, Pathological; Tolcapone