基因治疗用腺相关病毒载体的剂量效应与剂量控制

摘要/Abstract

摘要： 人类基因治疗需要在靶细胞适时、适量、安全的产生具有疗效的药物,这些正好是定量药理学的研究范畴。重组腺相关病毒载体(rAAV)具有的各种特性以及近来在规模化制备方面取得的进展使其逐渐成为基因治疗的理想载体。超过60项以AAV为载体的基因治疗已经完成或正在展开。其中,rAAV载体的剂量与基因表达效率以及临床疗效之间的关系是研究者关注的焦点之一。多数研究认为,在一定的剂量范围内,基因表达水平具有剂量依赖性。然而, 基因表达水平同时还受病毒载体构型、组织趋向性、细胞靶向性、注射途径, 甚至患者的年龄、性别等条件影响 ,基因表达水平还可受到其他药物的调控。因此,基因治疗实验过程中应结合定量药理学深入展开,解决基因治疗中的定量与药效之间的关系。

关键词: 基因治疗, 病毒载体, 剂量效应, 定量药理学, 临床治疗

Abstract: Human gene therapy needs to express exogenous DNA at the targeting cells, producing a practical and efficient therapeutic dosage at an approp-riate time (quantitative pharmacology)with a safe man-ner .Recombinant adeno-associated virus(rAAV)vec-tors possess a number of properties and recent progress in rAAV production made it rapidly become the reagent of choice for therapeutic gene transfer.Over 60 clinical trials of gene therapy based on rAAV have been carried out .The dose response reaction between rAAV vectors and gene expression activity or clinical outcome is one of major aspects of these trials.Most studies showed that vector genomes (vg)and gene expression had a concentration-dependent relationship during a certain scope .However, gene expression can be affected by viral serotypes, tissue tropisms, cell targeting , drug regulation, injection route , age and sex , etc .Thus, these aspects should be carefully considered by scienti-sts, pharmacologists and physicians during animal ex-periments or clinical trails.

Key words: gene therapy, viral vector, dose-re-sponse, quantitative pharmacology, clinical therapy

中图分类号:

R968

王启钊, 吕颖慧, 许瑞安. 基因治疗用腺相关病毒载体的剂量效应与剂量控制[J]. 中国临床药理学与治疗学, 2008, 13(10): 1182-1194.

WANG Qi-zhao, LV Ying-hui, XU Rui-an. Dose-response and control of adeno-associated viral vectors based preclinical and clinical gene therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(10): 1182-1194.

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