Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis

Transthyretin (TTR) is a tetrameric transport protein that causes amyloid formation if destabilized. ATTR ‐amyloidosis is a progressive systemic disease with polyneuropathy and cardiomyopathy as the most abundant manifestations. Approved treatment approaches comprise sequence‐specific mRNA degradation and tetramer stabilization. Ongoing clinical trials assess the potential of GalNAc formulations to improve the administration of small interfering RNA and antisense oligonucleotides. A future TTR‐stabilizer with the potential to cross the blood‐brain barrier is tolcapone. Amyloid‐directed antibodies aim at reducing the amyloid load. In this model disease for pathophysiology‐based treatmen t, further studies are needed to overcome remaining limitations including application burden and blood‐brain permeability. AbstractThe liver ‐derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild‐type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate‐limiting step of amyloidogenesis. Besides destabilizingTTR mutations, other genetic (RBP4,APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) fac...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Review Article Source Type: research