In vivo gene editing with YOLT-201 for transthyretin amyloid cardiomyopathy – an open-label, first-in-human clinical trial

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening disease driven by continuous hepatic production of misfolded transthyretin. Existing therapies slow progression but require chronic administration. YOLT-201 is an in vivo CRISPR-Cas9 gene-editing therapy delivered by lipid nanoparticles and designed for one-time suppression of TTR production. Purpose To evaluate the safety, pharmacodynamic activity, and early clinical effects of YOLT-201 in patients with ATTR-CM. Methods This is an ongoing open-label, first-in-human, single-ascending-dose phase 1 study (NCT06082050). Participants received a single intravenous dose of 0.1-1.0 mg/kg; selected participants underwent voluntary repeat dosing at 1.0 mg/kg. Primary endpoints were safety and tolerability. Key secondary endpoints included percentage change in serum TTR and exploratory clinical measures (NT-proBNP, six-minute walk distance, KCCQ score, NYHA class, cardiac biomarkers and cardiac imaging). Results Seven participants have been treated. No dose-limiting toxicities occurred and no participant discontinued treatment. Sixty-four adverse events were reported, predominantly mild or moderate. The most common AEs included transient liver enzyme elevations, increases in D-dimer, vitamin A deficiency and infusion-related reactions. One treatment-unrelated serious adverse event (malignant arrhythmia) resolved without sequelae. YOLT-201 produced rapid, deep, and dose-dependent TTR suppression, reaching median reductions of up to −96% at 1.0 mg/kg, durable through 36 weeks and sustained to week 52 in one participant. Repeat dosing restored pharmacodynamic response in both participants with inadequate initial suppression, including one achieving >90% knockdown sustained through 24 weeks. Early clinical signals were most evident at 1.0 mg/kg and following repeat dosing, including substantial reductions in NT-proBNP, improvements in six-minute walk distance in five participants (with gains of 125-209 m at 1.0 mg/kg), increases in KCCQ score in several participants (up to +20 points), improvement in NYHA functional class in one participant with stability in the remainder, and reductions in cardiac tracer uptake on 99mTc-PYP scintigraphy ranging from −3% to −22% at week 52, greatest in the 1.0 mg/kg cohort. Conclusion YOLT-201 demonstrated favourable safety and produced profound and durable suppression of serum TTR in this first-in-human study, with encouraging early improvements across biomarkers, functional capacity, patient-reported outcomes, and imaging. These findings support in vivo CRISPR-Cas9 editing as a potential one-time therapeutic strategy for ATTR-CM.