In Vivo CRISPR Gene Editing in Patients with Herpes Stromal Keratitis

Abstract In vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of HSV-1-targeting CRISPR formulation in the cornea of three patients with severe refractory herpes stromal keratitis (HSK) during corneal transplantation. Our study is an investigated initiated, open-label, single-arm, non-randomized interventional trial at a single center ( NCT04560790 ). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients. The HSV-1 remained undetectable during the study. Our preliminary clinical results suggest that in vivo gene editing targeting the HSV-1 genome holds acceptable safety as a potential therapy for HSK. One-Sentence Summary Our study is the first in vivo CRISPR therapy for treating infectious disease and the first virus-like particle (VLP)-delivered gene therapy, reporting clinical follow-up to 21 months in HSK patients without seeing virus relapse, HSK recurrence, and CRISPR-associated side effects.