First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers.
Here, the role of APOE was investigated with regard to the efficacy of Patisiran, the first LNP-siRNA recently approved for clinical use in patients having transthyretin amyloidosis (ATTR amyloidosis).
Transthyretin amyloidosis (ATTR amyloidosis) is a fatal systemic disease caused by amyloid deposits of misfolded transthyretin, leading to familial amyloid polyneuropathy and/or cardiomyopathy, or a rare oculoleptomeningeal amyloidosis.
In this study, we measured plasma neurofilament light chain (pNfL) concentration in 73 patients with ATTR and found that pNfL was significantly raised in ATTRm patients with peripheral neuropathy compared to healthy controls.
Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.
A total of 134 patients with wild-type ATTR (ATTRwt) (122 men; age 76 ± 7 years), 81 patients with hereditary-type ATTR (ATTRm) (60 men; age 69 ± 11 years), 44 patients with HCM (32 men; age 51 ± 13 years), and 12 asymptomatic mutation carriers (4 men; age 47 ± 10 years) were studied.
Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants.
AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.
Two subtypes predominate: systemic light-chain CA (ALCA) and transthyretin-derived CA (either wild type transthyretin amyloidosis [TTRwt] or mutant transthyretin amyloidosis [TTRm]).
Our findings of TTR variants in 17% of screened patients highlight the need for routine genetic testing in the evaluation of suspected ATTR amyloidosis.
In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.
Familial amyloid polyneuropathy (FAP) or ATTRv (amyloid TTR variant) amyloidosis is a fatal hereditary disease characterized by the deposition of amyloid fibrils composed of transthyretin (TTR).
For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAPVal30Met, decreasing mean AO by 6 years (95% confidence interval = -8.81 to -2.19, p = 0.001).
Transthyretin amyloidosis with polyneuropathy (ATTR-PN), a rare and progressive hereditary disorder, results from mutations in the gene coding for the transthyretin (TTR) protein that destabilize the protein's tetrameric structure.
Our study demonstrates that the escape of TTR monomers from the ERQC may underlie late-onset amyloidogenesis in patients and suggests that targeting ERQC could mitigate late-onset ATTR.