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Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis. Complete OTCD can result in hyperammonemic coma in the neonatal period which can rapidly become fatal. Current acute therapy involves dialysis; chronic therapy involves the stimulation of alternate nitrog...

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Autores principales: Wang, Lili, Wang, Huan, Morizono, Hiroki, Bell, Peter, Jones, David, Lin, Jianping, McMenamin, Deirdre, Yu, Hongwei, Batshaw, Mark L., Wilson, James M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321078/
https://www.ncbi.nlm.nih.gov/pubmed/21850052
http://dx.doi.org/10.1038/gt.2011.111
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author Wang, Lili
Wang, Huan
Morizono, Hiroki
Bell, Peter
Jones, David
Lin, Jianping
McMenamin, Deirdre
Yu, Hongwei
Batshaw, Mark L.
Wilson, James M.
author_facet Wang, Lili
Wang, Huan
Morizono, Hiroki
Bell, Peter
Jones, David
Lin, Jianping
McMenamin, Deirdre
Yu, Hongwei
Batshaw, Mark L.
Wilson, James M.
author_sort Wang, Lili
collection PubMed
description Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis. Complete OTCD can result in hyperammonemic coma in the neonatal period which can rapidly become fatal. Current acute therapy involves dialysis; chronic therapy involves the stimulation of alternate nitrogen clearance pathways; and the only curative approach is liver transplantation. AAV vector based gene therapy would add to current treatment options provided the vector delivers high level and stable transgene expression in liver without dose limiting toxicity. In this study, we employed an AAV2/8-based self-complementary (sc) vector expressing the murine OTC gene under a liver-specific thyroxine-binding globulin (TBG) promoter and examined the therapeutic effects in a mouse model of OTCD, the spf (ash) mouse. Seven days after a single intravenous injection of vector, treated mice showed complete normalization of urinary orotic acid, a measure of OTC activity. We further improved vector efficacy by incorporating a Kozak or Kozak-like sequence into mOTC cDNA which increased the OTC activity by 5- or 2-fold and achieved sustained correction of orotic aciduria for up to 7 months. Our results demonstrate that vector optimizations can significantly improve the efficacy of gene therapy.
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spelling pubmed-33210782012-10-01 Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors Wang, Lili Wang, Huan Morizono, Hiroki Bell, Peter Jones, David Lin, Jianping McMenamin, Deirdre Yu, Hongwei Batshaw, Mark L. Wilson, James M. Gene Ther Article Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis. Complete OTCD can result in hyperammonemic coma in the neonatal period which can rapidly become fatal. Current acute therapy involves dialysis; chronic therapy involves the stimulation of alternate nitrogen clearance pathways; and the only curative approach is liver transplantation. AAV vector based gene therapy would add to current treatment options provided the vector delivers high level and stable transgene expression in liver without dose limiting toxicity. In this study, we employed an AAV2/8-based self-complementary (sc) vector expressing the murine OTC gene under a liver-specific thyroxine-binding globulin (TBG) promoter and examined the therapeutic effects in a mouse model of OTCD, the spf (ash) mouse. Seven days after a single intravenous injection of vector, treated mice showed complete normalization of urinary orotic acid, a measure of OTC activity. We further improved vector efficacy by incorporating a Kozak or Kozak-like sequence into mOTC cDNA which increased the OTC activity by 5- or 2-fold and achieved sustained correction of orotic aciduria for up to 7 months. Our results demonstrate that vector optimizations can significantly improve the efficacy of gene therapy. 2011-08-18 2012-04 /pmc/articles/PMC3321078/ /pubmed/21850052 http://dx.doi.org/10.1038/gt.2011.111 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Lili
Wang, Huan
Morizono, Hiroki
Bell, Peter
Jones, David
Lin, Jianping
McMenamin, Deirdre
Yu, Hongwei
Batshaw, Mark L.
Wilson, James M.
Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title_full Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title_fullStr Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title_full_unstemmed Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title_short Sustained Correction of OTC Deficiency in Spf (ash) mice Using Optimized Self-complementary AAV2/8 Vectors
title_sort sustained correction of otc deficiency in spf (ash) mice using optimized self-complementary aav2/8 vectors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321078/
https://www.ncbi.nlm.nih.gov/pubmed/21850052
http://dx.doi.org/10.1038/gt.2011.111
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