Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy.

TitleLong-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy.
Publication TypeJournal Article
Year of Publication2019
AuthorsCE Nelson, Y Wu, MP Gemberling, ML Oliver, MA Waller, JD Bohning, JN Robinson-Hamm, K Bulaklak, RM Castellano Rivera, JH Collier, A Asokan, and CA Gersbach
JournalNat Med
Volume25
Start Page427
Issue3
Pagination427 - 432
Date Published03/2019
Abstract

Duchenne muscular dystrophy (DMD) is a monogenic disorder and a candidate for therapeutic genome editing. There have been several recent reports of genome editing in preclinical models of Duchenne muscular dystrophy1-6, however, the long-term persistence and safety of these genome editing approaches have not been addressed. Here we show that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of Duchenne muscular dystrophy for 1 year after a single intravenous administration of an adeno-associated virus that encodes CRISPR (AAV-CRISPR). We also show that AAV-CRISPR is immunogenic when administered to adult mice7; however, humoral and cellular immune responses can be avoided by treating neonatal mice. Additionally, we describe unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. This study shows the potential of AAV-CRISPR for permanent genome corrections and highlights aspects of host response and alternative genome editing outcomes that require further study.

DOI10.1038/s41591-019-0344-3
Short TitleNat Med