A SYNTHETIC, CHEMICALLY-MODIFIED RIBOZYME ELIMINATES AMELOGENIN, THE MAJOR TRANSLATION PRODUCT IN DEVELOPING MOUSE ENAMEL IN-VIVO
A SYNTHETIC, CHEMICALLY-MODIFIED RIBOZYME ELIMINATES AMELOGENIN, THE MAJOR TRANSLATION PRODUCT IN DEVELOPING MOUSE ENAMEL IN-VIVO
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DOI：
10.1002/j.1460-2075.1995.tb00207.x
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发表时间：
1995-11-01
期刊：
影响因子：
11.4
通讯作者：
PRYDZ, HP
中科院分区：
文献类型：
--
作者：
LYNGSTADAAS, SP;RISNES, S;PRYDZ, HP
核酶是能够以催化方式切割RNA靶分子的小RNA结构。设计的核酶可以靶向特定的mRNA，阻断它们的表达而不影响其他基因的正常功能。由于它们的特异性和催化作用模式，核酶是针对功能障碍或外源基因产物的治疗干预的理想试剂。在这里，我们报告了使用合成的化学修饰的核酶在体内“敲除"主要翻译产物的成功实验。设计用于切割釉原蛋白mRNA的核酶被注射到新生小鼠发育中的下颌磨牙附近，导致釉原蛋白合成的延长和特异性停滞，而不是由一般毒性引起的。不需要载体来辅助细胞摄取。釉原蛋白是高度保守的组织特异性蛋白质，在哺乳动物釉质生物矿化中起中心作用。在体内核酶处理的牙齿的超微结构分析表明，他们未能正常矿化釉质的发展，这些结果表明，合成的核酶可以非常有效地实现定时和本地化的“敲除”的重要基因产物在体内，并提出新的可能性抑制基因表达的研究和治疗目的。
Ribozymes are small RNA structures capable of cleaving RNA target molecules in a catalytic fashion. Designed ribozymes can be targeted to specific mRNAs, blocking their expression without affecting normal functions of other genes. Because of their specific and catalytic mode of action ribozymes are ideal agents for therapeutic interventions against malfunctioning or foreign gene products, Here we report successful experiments to 'knock out' a major translation product in vivo using synthesized, chemically modified ribozymes, The ribozymes, designed to cleave amelogenin mRNA, were injected close to developing mandibular molar teeth in newborn mice, resulting in a prolonged and specific arrest of amelogenin synthesis not caused by general toxicity, No carriers were required to assist cellular uptake, Amelogenins are highly conserved tissue-specific proteins that play a central role in mammalian enamel biomineralization. Ultrastructural analyses of in vivo ribozyme-treated teeth demonstrated their failure to develop normally mineralized enamel, These results demonstrate that synthesized ribozymes can be highly effective in achieving both timed and localized 'knock-out' of important gene products in vivo, and suggest new possibilities for suppression of gene expression for research and therapeutic purposes.