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摘要
我们报告了在组成型肝特异性启动子存在条件下,利用编码人胰岛素原基因的单次假腺相关病毒8型(ssAAV2/8)载体给药进行全身给药,对STZ诱导糖尿病小鼠高血糖进行校正。通过体内剂量滴定实验,我们确定最佳剂量范围,实现了保持正常的血糖含量,或保持小鼠至少9个月处于糖尿病状态,对某些动物能使其持续保持糖尿病状态超过1年,并伴随人类C-肽分泌和体重增加。胰岛素基因的DNA密码子进一步优化,导致在密码子优化治疗的动物血液中分泌约3-10倍的C肽,从而降低载体粒子数量,而使血糖水平降低至相同程度。胰岛素构成性分泌与载体的单次给药,对某些糖尿病患者具有治疗价值。
关键词: 基因治疗,糖尿病,胰岛素,AAV,密码子优化。
Current Gene Therapy
Title:Correction of Murine Diabetic Hyperglycaemia With A Single Systemic Administration of An AAV2/8 Vector Containing A Novel Codon Optimized Human Insulin Gene
Volume: 16 Issue: 1
Author(s): Gan Shu Uin, Notaridou Maria, Fu Zhen Ying, Lee Kok Onn, Sia Kian Chuan and Nathwani Amit Chunilal, Della Peruta Marco and Calne Roy Yorke
Affiliation:
关键词: 基因治疗,糖尿病,胰岛素,AAV,密码子优化。
摘要: We report the correction of hyperglycemia of STZ induced diabetic mice using one intravenous systemic administration of a single stranded serotype 8 pseudotyped adeno-associated virus (ssAAV2/8) vector encoding the human proinsulin gene under a constitutive liver specific promoter. In vivo dose titration experiments were carried out and we identified an optimal range that achieved maintenance of euglycaemia or a mild diabetic condition for at least 9 months and ongoing to beyond 1 year for some animals, accompanied by human C-peptide secretion and weight gain. Further DNA codon optimization of the insulin gene construct resulted in approximately 3-10 times more human C-peptide secreted in the blood of codon optimized treated animals thereby reducing the number of vector particles required to achieve the same extent of reduction in blood glucose levels as the non-codon optimized vector. The constitutive secretion of insulin achieved with a single administration of the vector could be of therapeutic value for some diabetic patients.
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Gan Shu Uin, Notaridou Maria, Fu Zhen Ying, Lee Kok Onn, Sia Kian Chuan and Nathwani Amit Chunilal, Della Peruta Marco and Calne Roy Yorke , Correction of Murine Diabetic Hyperglycaemia With A Single Systemic Administration of An AAV2/8 Vector Containing A Novel Codon Optimized Human Insulin Gene, Current Gene Therapy 2016; 16 (1) . https://dx.doi.org/10.2174/1566523216666160122113958
DOI https://dx.doi.org/10.2174/1566523216666160122113958 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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