Long-Term Correction of Ammonia Metabolism and Prolonged Survival in Ornithine Transcarbamylase-Deficient Mice Following Liver-Directed Treatment with Adeno-associated Viral Vectors
2006; Elsevier BV; Volume: 14; Issue: 1 Linguagem: Inglês
10.1016/j.ymthe.2006.03.009
ISSN1525-0024
AutoresDavid Moscioni, Hiroki Morizono, Robert McCarter, Adam W. Stern, Juan Cabrera‐Luque, Albert Hoang, Julio Sanmiguel, Di Wu, Peter Bell, Guangping Gao, Steven E. Raper, James M. Wilson, Mark L. Batshaw,
Tópico(s)Cytomegalovirus and herpesvirus research
ResumoThe purpose of this study was to determine the efficacy of novel recombinant adeno-associated viral (AAV) vector constructs in correcting metabolic defects in the liver in two strains of ornithine transcarbamylase (OTC)-deficient mice (spf and spf-ash). AAV vectors expressing mouse OTC were produced with capsids from AAV2 and the novel serotypes AAV7, 8, and 9. OTC-deficient mice were infused with these vectors as well as a control AAV2/8 vector expressing LacZ. In vivo activity of OTC was assessed by measuring a surrogate marker, urine orotate. The novel vectors restored orotate levels to virtually normal 15 days after infusion, and each persisted to 1 year posttreatment. Liver OTC enzyme activity in spf mice was substantially higher in animals receiving novel vectors compared to those receiving AAV2 vectors. Animals receiving novel OTC-expressing vectors lived longer than those treated with AAV2 OTC or untreated controls, and they were tolerant to a challenge with NH3 at 21 days and beyond, which caused severe morbidity in control OTC-deficient animals. Numerous mice, representative of all treatment groups followed for +250 days, were observed to have either nodules or discrete tumors in the liver, the etiology of which is the subject of a companion paper.
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