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Safety and efficacy of adeno-associated viral vector-mediated insulin gene transfer via portal vein to the livers of streptozotocin-induced diabetic Sprague-Dawley rats

Authors
 Young Mi Park  ;  Seonock Woo  ;  Geun Taek Lee  ;  Ji-Yun Ko  ;  Yongho Lee  ;  Zheng-Shan Zhao  ;  Hye Joo Kim  ;  Chul Woo Ahn  ;  Bong Soo Cha  ;  Kyung-Sup Kim  ;  Cheol Won Park  ;  Hyun Chul Lee 
Citation
 JOURNAL OF GENE MEDICINE, Vol.7(5) : 621-629, 2005 
Journal Title
 JOURNAL OF GENE MEDICINE 
ISSN
 1099-498X 
Issue Date
2005
MeSH
Animals ; Animals, Genetically Modified ; Blood Glucose/metabolism ; Cytoskeletal Proteins/pharmacology ; Dependovirus/genetics* ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/therapy* ; Gene Transfer Techniques* ; Genetic Therapy* ; Genetic Vectors* ; Glucose Tolerance Test ; Glycated Hemoglobin A/metabolism ; Insulin/genetics* ; Insulin/metabolism ; Liver/metabolism* ; Male ; Portal Vein ; Proinsulin/metabolism ; Pyrin ; Rats ; Rats, Sprague-Dawley ; Safety ; Treatment Outcome
Keywords
diabetes mellitus ; basal insulin ; gene therapy ; recombinant viral vectors
Abstract
BACKGROUND: Previous studies demonstrating the efficacy of insulin gene therapy have mostly involved use of adenoviral vectors or naked DNA to deliver the insulin gene. However, this procedure may not guarantee long-term insulin production. To improve the performance, we prepared recombinant adeno-associated viral vectors (rAAV) harboring the gene encoding a furin-modified human insulin under the cytomegalovirus (CMV) promoter [rAAV-hPPI(F12)]. METHODS: Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats were used as a diabetic animal model. The levels of blood glucose, insulin, and HbA1c were measured to test the effect. An intraperitoneal glucose tolerance test was performed to test the capability of blood glucose disposal. Immunohistochemical staining and Northern blot analyses were performed to survey the expression pattern of the therapeutic insulin gene. RESULTS: STZ-induced diabetic Sprague-Dawley rats infused via the portal vein with rAAV-hPPI(F12) produced human insulin and after a 6-h fast were normoglycemic for over 90 days post-treatment, whereas diabetic rats treated with recombinant adenoviral vector harboring the hPPI(F12) gene [rAV-hPPI(F12)] were normoglycemic only for days 3 to 13 post-treatment. Insulin mRNA was detected mainly in the liver of the rAAV-hPPI(F12)-treated diabetic rats. The glucose tolerance capability of the rAAV-hPPI(F12)-treated diabetic rats was comparable to that of non-diabetic rats, even without injection of recombinant insulin. Furthermore, blood HbA1c concentrations in rAAV-hPPI(F12)-treated diabetic rats were reduced to almost the normal level. Importantly, studies of rAV or rAAV vector-dependent side effects on the targeted liver strongly suggested that only rAAV treatment caused no side effects. CONCLUSIONS: These results demonstrate that our rAAV-mediated in vivo insulin gene therapy provides safer maintenance of the insulin gene expression required for long-term and thus more effective blood glycemic control.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/jgm.708/abstract
DOI
10.1002/jgm.708
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Ahn, Chul Woo(안철우) ORCID logo https://orcid.org/0000-0003-3733-7486
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Hyun Chul(이현철)
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/150041
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