Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa
Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa
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DOI：
10.1038/nm0898-967
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发表时间：
1998-08-01
期刊：
影响因子：
82.9
通讯作者：
LaVail, MM
中科院分区：
文献类型：
--
作者：
Lewin, AS;Drenser, KA;LaVail, MM
核酶，催化RNA分子，切割互补的mRNA序列，具有治疗显性遗传疾病的潜力。患有致盲性疾病常染色体显性视网膜色素变性（ADRP）的12%的美国患者在其视紫红质基因的密码子23（P23 H）处携带组氨酸取代脯氨酸（1），导致感光细胞因异常基因产物的合成而死亡。核酶可以区分并催化ADRP转基因大鼠模型中P23 H突变mRNA的体外破坏（参考文献2）。在这里，我们证明了在这个大鼠模型中的锤头状或发夹状核酶的体内表达大大减缓了感光细胞变性的速率至少三个月。无催化活性的对照核酶对视网膜变性的影响较小。通过用并入视杆视蛋白启动子的重组腺相关病毒（rAAV）转导来实现光感受器中核酶的细胞内产生。因此，核酶介导的突变mRNA切割可能是ADRP的有效治疗方法，也可能适用于其他遗传性疾病。
Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene(1), resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP (ref. 2). Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases.