Compositions and methods for altering a nucleobase in a transthyretin polynucleotide

Abstract

Compositions for modifying or editing a polynucleotide (e.g., a gene) and methods for using them to treat or prevent conditions associated with the extracellular deposition in various tissues of amyloid fibrils formed by the aggregation of misfolded transthyretin (TTR) proteins. Such conditions are disclosed, including, but not limited to, hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) and hereditary transthyretin amyloidosis cardiomyopathy (hATTR-CM), both associated with autosomal dominant mutations in the TTR gene, and an age-related cardiomyopathy associated with wild-type TTR proteins (ATTRwt), also known as senile cardiac amyloidosis. Compositions and methods for editing TTR polynucleotides using base-editing systems are disclosed.