title: Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome.
abstract: Ornithine transcarbamylase deficiency (OTCD), the most common and severe urea cycle disorder, is an excellent model for developing liver-directed gene therapy. No curative therapy exists except for liver transplantation which is limited by available donors and carries significant risk of mortality and morbidity. Adeno-associated virus 8 (AAV8) has been shown to be the most efficient vector for liver-directed gene transfer and is currently being evaluated in a clinical trial for treating hemophilia B. In this study, we generated a clinical candidate vector for a proposed OTC gene therapy trial in humans based on a self-complementary AAV8 vector expressing codon-optimized human OTC (hOTCco) under the control of a liver-specific promoter. Codon-optimization dramatically improved the efficacy of OTC gene therapy. Supraphysiological expression levels and activity of hOTC were achieved in adult spf(ash) mice following a single intravenous injection of hOTCco vector. Vector doses as low as 1×10(10) genome copies (GC) achieved robust and sustained correction of the OTCD biomarker orotic aciduria and clinical protection against an ammonia challenge. Functional expression of hOTC in 40% of liver areas was found in mice treated with a low vector dose of 1×10(9) GC. We suggest that the clinical candidate vector we have developed has the potential to achieve therapeutic effects in OTCD patients.
authors: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Lili
authors: L
authors: Wang
authors: Hiroki
authors: H
authors: Morizono
authors: Jianping
authors: J
authors: Lin
authors: Peter
authors: P
authors: Bell
authors: David
authors: D
authors: Jones
authors: Deirdre
authors: D
authors: McMenamin
authors: Hongwei
authors: H
authors: Yu
authors: Mark L
authors: ML
authors: Batshaw
authors: James M
authors: JM
authors: Wilson
mesh_terms: D000328:Adult; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism*; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D009963:Orotic Acid / Q000652:urine
chemical_list: D009963:Orotic Acid; D009954:Ornithine Carbamoyltransferase