Cutroneo Kenneth R, Chiu Jen-Fu
Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT 05405-0068, USA.
Int J Biochem Cell Biol. 2003 Jan;35(1):32-8. doi: 10.1016/s1357-2725(02)00166-8.
Considerable evidence has ensued on the importance of growth factors during regeneration both for cell replication and for stimulation of reparative cells to synthesize and secrete extracellular matrix components. During the healing process if the growth factor concentration is too high because of over-expression, abnormal wound healing and tissue fibrosis will occur. The growth factor concentration at the wound site may be controlled by gene therapy and the titration of gene dosage. However, if there is a narrow window between the beneficial effects and adverse effects of gene therapy, oligonucleotide approaches may be used concurrently with gene therapy to control growth factor concentration(s) at the wound site. Antisense oligos offer a method to control the concentration of growth factors at the level of translation. A novel method using sense oligos to the proalpha1 (I) collagen gene to inhibit gene transcription and collagen synthesis has recently been reported. The exogenous modified oligodeoxynucleotide competes with the cis-element (i.e. the transforming growth factor-beta (TGF-beta) element) in the distal 5'-flanking region of the proalpha1 (I) collagen gene for the trans-acting factor (i.e. the TGF-beta activator protein complex), thereby down regulating promoter activity of the proalpha1 (I) collagen gene and inhibiting type I collagen synthesis. The oligonucleotide approaches, both antisense and sense therapies, may be used to regulate over-expression of growth factors and thereby either eliminate or lessen the potential adverse effects of gene therapy.
关于生长因子在再生过程中对细胞复制以及刺激修复细胞合成和分泌细胞外基质成分的重要性，已有大量证据。在愈合过程中，如果由于过度表达导致生长因子浓度过高，将会出现异常伤口愈合和组织纤维化。伤口部位的生长因子浓度可通过基因治疗和基因剂量滴定来控制。然而，如果基因治疗的有益效果和不良效果之间的差距很小，可以同时使用寡核苷酸方法与基因治疗来控制伤口部位的生长因子浓度。反义寡核苷酸提供了一种在翻译水平控制生长因子浓度的方法。最近报道了一种使用针对原α1（I）胶原基因的正义寡核苷酸来抑制基因转录和胶原合成的新方法。外源性修饰寡脱氧核苷酸与原α1（I）胶原基因5'-侧翼远端区域的顺式元件（即转化生长因子-β（TGF-β）元件）竞争反式作用因子（即TGF-β激活蛋白复合物），从而下调原α1（I）胶原基因的启动子活性并抑制I型胶原合成。寡核苷酸方法，包括反义疗法和正义疗法，可用于调节生长因子的过度表达，从而消除或减轻基因治疗的潜在不良影响。
