title: Long-term correction of ammonia metabolism and prolonged survival in ornithine transcarbamylase-deficient mice following liver-directed treatment with adeno-associated viral vectors.
abstract: The 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.
authors: Gene Therapy Program, Division of Medical Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: David
authors: D
authors: Moscioni
authors: Hiroki
authors: H
authors: Morizono
authors: Robert J
authors: RJ
authors: McCarter
authors: Adam
authors: A
authors: Stern
authors: Juan
authors: J
authors: Cabrera-Luque
authors: Albert
authors: A
authors: Hoang
authors: Julio
authors: J
authors: Sanmiguel
authors: Di
authors: D
authors: Wu
authors: Peter
authors: P
authors: Bell
authors: Guang-Ping
authors: GP
authors: Gao
authors: Steven E
authors: SE
authors: Raper
authors: James M
authors: JM
authors: Wilson
authors: Mark L
authors: ML
authors: Batshaw