Advances in the Treatment of Cardiac Amyloidosis

Macedo, Ariane Vieira Scarlatelli; Schwartzmann, Pedro Vellosa; Gusmão, Breno Moreno de; Melo, Marcelo Dantas Tavares de; Coelho‐Filho, Otávio R.

doi:10.1007/s11864-020-00738-8

Cited by 39 publications

(67 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…135 Among them, advances in immunotherapy that inhibit AL or TTR production, amyloid fibril formation and remove existing fibril deposits have improved the clinical outcomes in these patients. 136 A number of immunomodulatory agents (pomalidomide, thalidomide), small interfering RNA (patisiran), antisense oligonucleotides (inotersen), TTR tetramer stabilizers (tafamidis, tolcapone, AG10) are actively being tested in clinical trials and show beneficial effects. 137 In addition, monoclonal antibody technology is a recent therapeutic approach in the treatment of cardiac amyloidosis with a favourable safety profile, well-tolerability and highly clinical effectiveness.…”

Section: Other Novel Anti-misfolding Protein Strategiesmentioning

confidence: 99%

“…In the recent past, a number of promising therapies have emerged to rescue specific amyloidosis: AL and ATTR 135 . Among them, advances in immunotherapy that inhibit AL or TTR production, amyloid fibril formation and remove existing fibril deposits have improved the clinical outcomes in these patients 136 . A number of immunomodulatory agents (pomalidomide, thalidomide), small interfering RNA (patisiran), antisense oligonucleotides (inotersen), TTR tetramer stabilizers (tafamidis, tolcapone, AG10) are actively being tested in clinical trials and show beneficial effects 137 .…”

Section: Anti‐misfolding Protein Strategies In Cardiovascular Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

The long and winding road to target protein misfolding in cardiovascular diseases

Diteepeng

Monte

Luciani

2021

Eur J Clin Investigation

View full text Add to dashboard Cite

Background: In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. Design: In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. Results: In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. Conclusions: At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians. K E Y W O R D Samyloid, cardiovascular diseases, oligomer, protein misfolding, therapy, unfolded protein responses 2 of 17 | DITEEPENG ET al.

show abstract

Section: Other Novel Anti-misfolding Protein Strategiesmentioning

confidence: 99%

Section: Anti‐misfolding Protein Strategies In Cardiovascular Diseasesmentioning

confidence: 99%

The long and winding road to target protein misfolding in cardiovascular diseases

Diteepeng

Monte

Luciani

2021

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

“…This is achieved since the antibody (misTTR) targets the residues 89-97 in the polypeptide chain, which are buried in the TTR tetramer, but it is exposed in the monomer, inhibiting fibrillogenesis of misfolded TTR under micromolar concentrations (Galant et al, 2016). This antibody has already entered into phase I clinical trials in ATTRv patients (Macedo et al, 2020).…”

Section: Immunotherapymentioning

confidence: 99%

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Bezerra

Saraiva

Almeida

2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

show abstract

“…Nonsustained VT (NSVT) was not identified here as a risk factor for appropriate shocks, but patient selection was guided by its presence: 51% of the patients had NSVT.Treatment for these patients is different depending on amyloid subtype, and probably between centers. Treatment has also been evolving in recent years, with the increasing use of stem cell transplant for AL amyloidosis6 and tafamidis 7 for TTR amyloidosis, resulting in a moving target and thus making comparisons or pooling of cohorts from different eras difficult.The question of how much benefit patients with CA derive fromICDs remains open. The rate of appropriate shocks in this pooled population was 18%, lower than in ICD trials in patients with ischemic or nonischemic cardiomyopathy.…”

mentioning

confidence: 99%

“…Treatment for these patients is different depending on amyloid subtype, and probably between centers. Treatment has also been evolving in recent years, with the increasing use of stem cell transplant for AL amyloidosis 6 and tafamidis 7 for TTR amyloidosis, resulting in a moving target and thus making comparisons or pooling of cohorts from different eras difficult.…”

mentioning

confidence: 99%