Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma

Nelson, Luke T.; Paxman, Ryan J; Xu, Jin; Webb, Bill; Powers, Evan T.

doi:10.1080/13506129.2020.1808783

Cited by 25 publications

(11 citation statements)

References 43 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Diflunisal acted as a tetramer stabilizer for the treatment of ATTR-CM, as the associated survival benefits were reported to be similar to those of Tafamidis (Maurer et al, 2018 ; Ibrahim et al, 2022 ). AG10 stabilized TTR tetramer by forming H-bonds with S117 (Zhou et al, 2020 ), and AG10 treatment was well-tolerated, achieved target plasma concentrations, and demonstrated near-complete stabilization of TTR (Judge et al, 2019 ; Nelson et al, 2021 ). In this work, it was found that E61K-TTR homozygous proteins and E61K: WT-TTR heterozygous tetramers might respond to current kinetic stabilizers less effectively compared to WT-TTR because full inhibition of fibril formation could be achieved for WT-TTR based on previously reported in vitro results.…”

Section: Discussionmentioning

confidence: 99%

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Chu

Wang²,

Tang³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation.Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration.Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Chu

Wang²,

Tang³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The concept that greater stabilization of TTR by therapeutic molecules with different binding sites may translate into better outcomes may be oversimplistic. In a recent publication, Nelson et al ( 15 ) performed a blinded potency comparison the ability of tafamidis, AG10, and tolcapone (a repurposed anti-Parkinsonian drug which stabilizes TTR) at levels equivalent to those obtained in the human in clinically used doses. They concluded that, although AG10 was 4 times more potent than tafamidis at a fixed plasma concentration, the oral administration in humans of 80 mg tafamidis as a single-dose daily (the U.S. Food and Drug Administration–approved dose) was equivalent to the clinical trial dose of 800 mg twice daily of AG10, as both doses reduce the rate of TTR wild-type tetramer dissociation by <96%.…”

Section: Discussionmentioning

confidence: 99%

Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy

Falk¹,

Haddad²,

Walker³

et al. 2021

JACC: CardioOncology

View full text Add to dashboard Cite

Background Transthyretin amyloid (ATTR) cardiomyopathy is slowed by tafamidis, which stabilizes the TTR molecule and reduces the formation of amyloidogenic oligomers. Stabilizers in clinical doses raise serum TTR, which may be a surrogate for the degree of stabilization. Objectives This study aims to determine, in a non-trial, unselected population of patients with ATTR cardiomyopathy, the effect of tafamidis on serum levels of TTR, and to compare these with published data of changes in TTR. Methods TTR levels were measured before therapy and 3 to 12 months following initiation of tafamidis therapy in all patients seen between May 20, 2019, and March 1, 2021, who had a follow-up visits within 12 months of therapy initiation. Results Among 72 patients with ATTR cardiomyopathy (67 patients with wild-type and 5 patients with variant TTR), administration of tafamidis increased serum TTR from 21.8 mg ± 0.7 mg/dL to 29.3 ± 0.86 mg/dL, an increase of 34.5%. In 5 patients with variant TTR, the increase was 70.9%, compared to 32.0% in the wild-type patients. Mean N-terminal pro-brain natriuretic peptide increased over a mean follow-up of 21 ± 1.2 weeks, but the change was not statistically significant. Over the same period there was a small increase in high-sensitivity troponin T that was of borderline statistical significance (P = 0.057). Conclusions Tafamidis consistently increases serum TTR levels in patients with ATTR cardiomyopathy, consistent with its effect on stabilizing TTR. Measurement of TTR level change post-TTR stabilizing therapy might be a surrogate for stabilization and could be a more accurate measure of drug efficacy than an in vitro nonphysiologic test of stabilization.

show abstract

“…Both FDA and EMA then approved tafamidis for the treatment of ATTR-CA [ 17 , 41 ]. AG10 has a greater affinity for TTR than tafamidis and achieves near-complete TTR stabilization in patients with ATTR-CA [ 48 ], but has a shorter half-life [ 49 ].…”

Section: Transthyretin Amyloidosis: General Conceptsmentioning

confidence: 99%

Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

et al. 2022

View full text Add to dashboard Cite

Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. “Amyloid seeds” are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.

show abstract

Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma

Cited by 25 publications

References 43 publications

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy

Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

Contact Info

Product

Resources

About