Permanent and efficient inactivation of the TTR gene by genome editing is the aim of a novel therapeutic approach currently being investigated for the treatment of a rare congenital disease, transthyretin amyloidosis. Specifically, a CRISPR/Cas9-based therapeutic agent is for the first time directly transferred into the human body, encapsulated in liposomes. Interim results of the phase I study performed by researchers in the United Kindom and New Zealand support the efficacy and safety of the agent, NTLA-2001.

More than 100 different pathogenic variants in TTR are known to cause the hereditary form of ATTR amyloidosis. The genetic defect leads to misfolding of the encoded protein, transthyretin. The defective protein forms amyloid fibres and progressively accumulates in heart and nerve tissue, resulting in dysfunction of the affected organs. Transthyretin is almost exclusively produced in the liver. Therefore, the researchers aimed at knocking out the gene directly in the liver, so that the body will only produce a negligible amount of TTR protein. To achieve this, they packed the CRISPR/Cas9 molecule with a guide RNA specifically targeting the TTR gene into liposomes and administered them by intravenous infusion. In the blood, these liposomes were naturally modified by certain proteins and were then directly taken up by liver cells via specific receptors. Six patients with hereditary transthyretin amyloidosis with polyneuropathy received a single injection of the agent either at a low or a slightly higher dose. After 28 days, all patients showed a decrease in TTR serum level, ranging from a mean reduction of 52 % (low dosage) to 87 % (higher dosage). No serious adverse events were reported.

The results of the study sponsored by Intellia Therapeutics and Regeneron Pharmaceuticals have been published in The New England Journal of Medicine.