Abstract
ATTR amyloidosis is a systemic, debilitating and fatal disease caused by transthyretin (TTR) amyloid accumulation. RNA interference (RNAi) is a clinically validated technology that may be a promising approach to the treatment of ATTR amyloidosis. The vast majority of TTR, the soluble precursor of TTR amyloid, is expressed and synthesized in the liver. RNAi technology enables robust hepatic gene silencing, the goal of which would be to reduce systemic levels of TTR and mitigate many of the clinical manifestations of ATTR that arise from hepatic TTR expression. To test this hypothesis, TTR-targeting siRNAs were evaluated in a murine model of hereditary ATTR amyloidosis. RNAi-mediated silencing of hepatic TTR expression inhibited TTR deposition and facilitated regression of existing TTR deposits in pathologically relevant tissues. Further, the extent of deposit regression correlated with the level of RNAi-mediated knockdown. In comparison to the TTR stabilizer, tafamidis, RNAi-mediated TTR knockdown led to greater regression of TTR deposits across a broader range of affected tissues. Together, the data presented herein support the therapeutic hypothesis behind TTR lowering and highlight the potential of RNAi in the treatment of patients afflicted with ATTR amyloidosis.
Highlights
Transthyretin (TTR) is a 127 amino acid, 55-kDa homotetrameric serum transport protein that is primarily expressed in the liver [1,2,3]
In this report we describe preclinical data that supports the therapeutic hypothesis that RNA interference (RNAi)-mediated depletion of the disease-causing TTR protein could lead to reduced TTR aggregation/deposition and thereby support the use of RNAi as a promising approach for the treatment of ATTR amyloidosis
Results siTTR silences wt and mutant TTR variants with similar efficacy and potency The RNAi therapeutic candidates currently in the clinic and those used in pre-clinical studies described in this report target a conserved region in the 30-untranslated region (30-UTR) of the TTR gene that does not overlap with any of the documented TTR variants [40]
Summary
Transthyretin (TTR) is a 127 amino acid, 55-kDa homotetrameric serum transport protein that is primarily expressed in the liver [1,2,3]. TTR-mediated amyloidosis (ATTR amyloidosis) is a progressive, systemic and fatal disease resulting from the damage caused by the extrahepatic deposition of insoluble TTR fibrils [12,13,14]. Manifestation of the hereditary ATTR amyloidosis disease phenotype is somewhat heterogeneous and is a direct result of the specific amyloidogenic mutation. In contrast to hereditary ATTR amyloidosis, wild-type ATTR amyloidosis results from the misfolding of wt TTR protein with deposition occurring predominantly in the heart [13,21]. Clinical presentation of wild-type ATTR amyloidosis, which includes carpal tunnel syndrome and cardiomyopathy, typically occurs much later in life relative to the hereditary forms, and likely reflects the fact that wt TTR is less prone to misfolding than other amyloidogenic variants
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