New Treatments for Amyloidosis Neuropathy

Peripheral neuropathy is a type of neurological disorder in which patients with complex inherited neurological defects present significant phenotype in the peripheral nervous system. Hereditary amyloidogenic transthyretin (hATTR) neuropathy is typical polyneuropathy caused by single-nucleotide variants in the gene encoding transthyretin (TTR) and leads to transthyretin misfoldingand systemic deposition of amyloid. One of the clinical hallmarks of hATTR neuropathy is polyneuropathy of the destructionof the somatic and autonomic peripheral nervous system, leading to loss of autonomy. Progressive amyloid accumulation alsocauses multi-organ dysfunction and death. There are many therapeutics that have been proposed and developed in these years.These therapies aim to reduce or eliminate hATTR from the plasma, stabilize the hATTR to prevent deposition, and dissolutethe amyloid misfolding matrix. Recently, gene therapy strategy is being deployed to treat recessive genetic disorders by eliminatingthe expression of the mutated genes. Thus, gene-silencing approaches have been used to manage this amyloidosis neuropathyin the broad stages and produce some degree of improvement of this disease. Food and Drug Administration (FDA) approvedInotersen (an antisense oligonucleotide (ASO)) and patisiran (a small interfering ribonucleic acid (siRNA) for the treatment ofhATTR polyneuropathy to suppress hATTR expression. Inotersen, a 2’-O-methoxyethylmodified ASO, which acts by reducingthe production of transthyretin, and has been demonstrated to improve the quality of life in early hereditary transthyretin amyloidosis polyneuropathy. I here focus on the RNA-targeted therapy with particular emphasis on the molecular mechanisms bywhich antisense oligonucleotide can be designed to modulate transthyretin RNA function for being a novel therapy for hereditaryamyloidosis neuropathy