Myocyte-mediated Arginase Expression Controls Hyperargininemia but not Hyperammonemia in Arginase-deficient Mice

被引:23
|
作者
Hu, Chuhong [1 ]
Kasten, Jennifer [1 ]
Park, Hana [1 ]
Bhargava, Ragini [1 ]
Tail, Denise S. [1 ]
Grody, Wayne W. [2 ,3 ]
Nguyen, Quynh G. [4 ]
Hauschka, Stephen D.
Cederbaum, Stephen D. [3 ,5 ,6 ,7 ,8 ]
Lipshutz, Gerald S. [1 ,6 ,7 ,8 ,9 ,10 ,11 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA
[4] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA
[7] Univ Calif Los Angeles, David Geffen Sch Med, Intellectual & Dev Disabil Res Ctr, Los Angeles, CA 90095 USA
[8] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci, Los Angeles, CA 90095 USA
[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA
[11] Univ Calif Los Angeles, David Geffen Sch Med, Broad Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
DEPENDENT ADENOVIRAL VECTOR; NEONATAL GENE-THERAPY; NITRIC-OXIDE; REGULATORY CASSETTES; IMMUNE-RESPONSES; TERM CORRECTION; HEMOPHILIA-A; MOUSE; SKELETAL; MUSCLE;
D O I
10.1038/mt.2014.99
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia that cause neurological impairment and growth retardation. We previously developed a neonatal mouse adeno-associated viral vector (AAV) rh10-mediated therapeutic approach with arginase expressed by a chicken beta-actin promoter that controlled plasma ammonia and arginine, but hepatic arginase declined rapidly. This study tested a codon-optimized arginase cDNA and compared the chicken beta-actin promoter to liver- and muscle-specific promoters. ARG1(-/-) mice treated with AAVrh10 carrying the liver-specific promoter also exhibited long-term survival and declining hepatic arginase accompanied by the loss of AAV episomes during subsequent liver growth. Although arginase expression in striated muscle was not expected to counteract hyperammonemia, due to muscle's lack of other urea cycle enzymes, we hypothesized that the postmitotic phenotype in muscle would allow vector genomes to persist, and hence contribute to decreased plasma arginine. As anticipated, ARG1(-/-) neonatal mice treated with AAVrh10 carrying a modified creatine kinase-based muscle-specific promoter did not survive longer than controls; however, their plasma arginine levels remained normal when animals were hyperammonemic. These data imply that plasma arginine can be controlled in arginase deficiency by muscle-specific expression, thus suggesting an alternative approach to utilizing the liver for treating hyperargininemia.
引用
收藏
页码:1792 / 1802
页数:11
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