Development of disease modifying therapies to ameliorate hereditary ATTR amyloidosis

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  • Sekijima Yoshiki
    Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine

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  • 遺伝性ATTRアミロイドーシスの病態に基づいた疾患修飾療法の開発

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<p>Transthyretin (TTR) is a representative amyloidogenic protein in humans. TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, then misfold and aggregate into amyloid fibrils, which results in autosomal dominant hereditary ATTR amyloidosis. Patients with hereditary ATTR amyloidosis show progressive sensorimotor neuropathy, autonomic dysfunction, cardiomyopathy, cerebral amyloid angiopathy, and ocular amyloidosis. In the natural course, patients die 10 to 15 years after the onset due to malnutrition, infection, or cardiac failure. Liver transplantation used to be the only disease modifying therapy for hereditary ATTR amyloidosis, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates because of their age and/or advanced disease status. Recently, clinical effects of TTR tetramer stabilisers, tafamidis and diflunisal, were demonstrated in randomized controlled trials, and tafamidis has been approved for the treatment of hereditary ATTR amyloidosis in more the 30 countries. In addition, gene therapies with small interfering RNAs (siRNAs) and antisense oligonucleotides are promising strategies to ameliorate hereditary ATTR amyloidosis. Patisiran is an investigational RNA interference (RNAi) therapeutic agent that binds to a conserved sequence in the TTR messenger RNA in the liver. The results of phase III clinical trial of patisiran was disclosed at the end of 2017, which showed its excellent efficacy and tolerability in hereditary ATTR amyloidosis patients.</p>

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