Invivogenomeeditingpartiallyrestoresalpha1-antitrypsinin amurinemodelofAATdeficiency.

CRISPRgenomeeditingholds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with Alpha-1 Antitrypsin (AAT)deficiencydevelop progressive lung disease due to the loss ofAAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediatedAATcorrection in the liver, whereAATis primarily expressed, can correct either or both defects. Here we show that AAV delivery of CRISPR can effectively correct Z-AATmutation in the liver of a transgenic mousemodel. Specifically, we co-injected two AAV: one expressing Cas9 and another encoding anAATguide RNA and homology-dependent repair template. In both neonate and adult mice, this treatmentpartiallyrestored M-AATin the serum. Furthermore, deep sequencing confirmed both indel mutations and precise gene correction in the liver, permitting careful analysis of geneeditingevents invivo. This study demonstrates a proof-of-concept for the application of CRISPR-Cas9 technology to correctAATmutations invivoand validates continued exploration of this approach for the treatment of patients withAATdeficiency.