Treating hereditary transthyretin amyloidosis: Present & future challenges.

ABSTRACT

Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic gain-of function (GOF) disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited and consisted mainly in liver transplantation and TTR-stabilizers. In the last few years, ATTRv has been at the center of major therapeutic breakthroughs, including development of effective small interfering RNA (siRNA) and antisense oligonucleotide (ASO) treatments targeting liver TTR mRNA. Both siRNA (patisiran) and ASO (inotersen) treatments are now commercially available and have dramatically improved ATTRv neurological outcome. Ongoing clinical trials currently evaluate another siRNA, vutrisiran and a novel ASO formulation, eplontersen. A CRISPR-Cas9-based TTR gene editing treatment is also currently evaluated, with encouraging preliminary results. These recent therapeutic developments demonstrate the shifting paradigm of ATTRv, a previously untreatable and lethal disorder and provide a proof-of-concept for developing siRNA, ASO and CRISPR-Cas9 treatments for other GOF genetic disorders.