Clinical safety and tolerability of in vivo gene editing drug ART001 for ATTR amyloidosis

Background ATTR amyloidosis is a disease caused by abnormal deposition of TTR (transthyretin) protein in tissues. ART001 is an in vivo gene therapy drug using lipid nanoparticle (LNP) to deliver mRNA encoding SpCas9 ( Streptococcus pyogenes Cas9) and a single guide RNA (sgRNA) for knocking-out of the TTR gene in hepatocytes and reducing serum TTR levels. Methods In an investigator-initiated trial (IIT) of ART001 for 10 ATTR Amyloidosis patients, each patient was given one dose of ART001 which ranged from 0.05 mg/kg to 1.0 mg/kg. The aim was to evaluate ART001’s safety, side effects, PK, PD, and efficacy based on circulating TTR protein levels. Results At 0.7 mg/kg in 3 subjects and 1 mg/kg in 3 subjects, TTR protein reductions averaged 84 and 92% at 72 weeks. No infusion-related reactions (IRRs), serious adverse events (SAEs) or serious adverse reactions (SARs) were observed. Conclusion A single injection of ART001 achieved 80% TTR knock-down at doses 0.5 mg/kg and lasted for at least 72 weeks without IRRs, SARs or SAEs. ART001 has the potential to be a safe, effective and permanent therapeutic option for ATTR Amyloidosis patients. (Funded by Accuredit Therapeutics). Clinical trial registration Trial registration: ChiCTR, ChiCTR2400081216. Registered 26 th Feb, 2024 - retrospectively registered, https://www.chictr.org.cn/showprojEN.html?proj=210566 .