کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1998619 | 1065818 | 2012 | 9 صفحه PDF | دانلود رایگان |
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 spfash mice following a single intravenous injection of hOTCco vector. Vector doses as low as 1 × 1010 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 × 109 GC. We suggest that the clinical candidate vector we have developed has the potential to achieve therapeutic effects in OTCD patients.
► Codon optimization significantly improves OTC protein expression levels and activity.
► The clinical candidate AAV8 vector has high transduction efficiency and efficacy.
► Robust and sustained correction in OTCD mice by a sc AAV2/8 vector expressing hOTC.
► Detection of functional enzyme from each persisting vector genome.
Journal: Molecular Genetics and Metabolism - Volume 105, Issue 2, February 2012, Pages 203–211