Vutrisiran

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) indicated for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTR). Hereditary ATTR is caused by mutations in the transthyretin (TTR) gene that destabilize the TTR protein. TTR proteins are primarily expressed in the liver, acting as carriers of vitamin A. TTR exists as a tetramer (four monomers or subunits), and is composed of 127 amino acids. Mutations in the TTR gene lead to the dissociation of the TTR tetramer into monomers. TTR monomers misfold, aggregate and form amyloid fibrils that deposit in peripheral and autonomic nerves, heart, and other organs.

Vutrisiran targets wild-type and mutant TTR messenger RNA (mRNA) and promotes its degradation. This decreases the serum levels of TTR protein and lowers the amount of amyloid fibril deposits in patients with hereditary ATTR. Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a molecule that binds to the asialoglycoprotein receptors (ASGPR) in hepatocytes. Therefore, the vutrisiran-GalNAc conjugate targets TTR mRNA in the liver.