Rossi J J, Elkins D, Taylor N, Zaia J, Sullivan S, Deshler J O
Department of Molecular Genetics, Beckman Research Institute of the City of Hope, Duarte, CA 91010.
Antisense Res Dev. 1991 Fall;1(3):285-8.
Antisense catalytic RNAs that specifically base-pair with and cleave target RNA sequences have potential for use as therapeutic agents against viral as well as endogenous gene expression. With the ultimate goal of developing anti-human immunodeficiency virus type 1 (HIV-1) ribozymes for therapeutic use, we have been exploring ways to improve upon the functional activity of ribozymes in living cells. This is being done by the systematic exploration of parameters that affect antisense, and hence ribozyme, function. These include target accessibility, stability of the catalyst, methods for delivery, and intracellular localization of the ribozyme. In addition, we have been examining the kinetic consequences of having extra, nontargeted sequences appended to the ribozyme flanking sequences. Perhaps the single most important consideration for ribozyme effectiveness in an intracellular environment is the accessibility of the target RNA for cleavage. By exploiting the mechanisms by which naturally occurring antisense RNAs interact with their target sequences, we hope to be able to address this problem of targeting and fully capitalize upon the potential of ribozymes as therapeutic agents.
能与靶RNA序列特异性碱基配对并切割靶RNA序列的反义催化RNA有潜力用作抗病毒及内源性基因表达的治疗剂。怀着开发用于治疗的抗1型人类免疫缺陷病毒（HIV-1）核酶的最终目标，我们一直在探索提高核酶在活细胞中功能活性的方法。这是通过系统探索影响反义以及核酶功能的参数来实现的。这些参数包括靶标可及性、催化剂稳定性、递送方法以及核酶的细胞内定位。此外，我们一直在研究在核酶侧翼序列附加额外的非靶向序列的动力学后果。在细胞内环境中，核酶有效性的单一最重要考量因素可能是靶RNA对于切割的可及性。通过利用天然存在的反义RNA与其靶序列相互作用的机制，我们希望能够解决靶向问题，并充分利用核酶作为治疗剂的潜力。
