Treatment of ATTR Amyloidosis: From Stabilizers to Gene Editing

Advances in noninvasive diagnosis, coupled with the development of effective treatments, have shifted transthyretin amyloidosis (ATTR) from a rare and untreatable disease to a relatively prevalent condition. Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. TTR stabilizers have become the first ever treatment to improve survival in ATTR-CM and have been recommended in guidelines from the International Societies of Cardiology worldwide. The emergence of novel gene silencing and gene editing therapies has rapidly expanded the armamentarium of treatments available for ATTR amyloidosis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Novel in vivo CRISPR-Cas9 gene editing therapy, transported by a lipid nanoparticle-mediated delivery system, has the potential to achieve near-complete and permanent knockdown of both wild-type and variant TTR expression after a single intravenous administration and prevent subsequent formation of pathogenic ATTR amyloid fibrils. Targeting TTR production has resulted in tremendous improvements in patient outcomes without evidence of any serious adverse clinical consequences in the short to medium term of depletion of circulating TTR. However, important questions remain including whether combining these agents (i.e., gene silencers with TTR stabilizer) could augment their therapeutic efficacy. A wide horizon of possibility is unfolding.