Abstract:
:Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder associated with high mortality. Although a promising treatment for late-onset OTC deficiency, adeno-associated virus (AAV) neonatal gene therapy would only provide short-term therapeutic effects as the non-integrated genome gets lost during hepatocyte proliferation. CRISPR-Cas9-mediated homology-directed repair can correct a G-to-A mutation in 10% of OTC alleles in the livers of newborn OTC spfash mice. However, an editing vector able to correct one mutation would not be applicable for patients carrying different OTC mutations, plus expression would not be fast enough to treat a hyperammonemia crisis. Here, we describe a dual-AAV vector system that accomplishes rapid short-term expression from a non-integrated minigene and long-term expression from the site-specific integration of this minigene without any selective growth advantage for OTC-positive cells in newborns. This CRISPR-Cas9 gene-targeting approach may be applicable to all patients with OTC deficiency, irrespective of mutation and/or clinical state.
journal_name
Sci Advjournal_title
Science advancesauthors
Wang L,Yang Y,Breton C,Bell P,Li M,Zhang J,Che Y,Saveliev A,He Z,White J,Latshaw C,Xu C,McMenamin D,Yu H,Morizono H,Batshaw ML,Wilson JMdoi
10.1126/sciadv.aax5701subject
Has Abstractpub_date
2020-02-12 00:00:00pages
eaax5701issue
7issn
2375-2548pii
aax5701journal_volume
6pub_type
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