Transthyretin gene (TTR)

The Transthyretin (TTR) gene, located on chromosome 18, encodes a 127-amino acid transport protein primarily synthesized in the liver that carries thyroxine and retinol-binding protein (UniProt: P02766). Mutations in this gene, or the aging process in wild-type cases, cause the TTR protein to misfold and aggregate into amyloid fibrils, which deposit in tissues such as the peripheral nerves and heart (NIH: GARD). This process leads to transthyretin amyloidosis (ATTR), a progressive and fatal disease characterized by polyneuropathy and cardiomyopathy. Targeting the TTR gene directly within hepatocyte nuclear DNA represents a potentially curative approach using gene-editing technologies like CRISPR/Cas9, such as the investigational therapy NTLA-2001 (Gillmore et al., NEJM 2021). By introducing site-specific double-strand breaks, these therapies aim to knock out the gene and permanently reduce the production of both mutant and wild-type TTR protein. This strategy addresses the root cause of the disease by significantly lowering the circulating levels of the precursor protein responsible for amyloid formation.

Other names

Prealbumin genePALBTBPAATTRAmyloidosis transthyretin-type gene

CRISPR/Cas9-mediated gene knockout via non-homologous end joining (NHEJ) following a site-specific double-strand break in the TTR gene within hepatocytes, leading to permanent reduction in transthyretin protein production.