Sarra G M, Stephens C, de Alwis M, Bainbridge J W, Smith A J, Thrasher A J, Ali R R
Department of Molecular Genetics, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK.
Hum Mol Genet. 2001 Oct 1;10(21):2353-61. doi: 10.1093/hmg/10.21.2353.
The retinal degeneration slow (rds or Prph2(Rd2/Rd2)) mouse, a model of recessive retinitis pigmentosa, lacks a functional gene encoding peripherin 2. This membrane glycoprotein is required for the formation of photoreceptor outer segment discs. The striking feature of the rds mouse is the complete failure to develop outer segments. We have previously examined the short-term effect of gene replacement therapy using an adeno-associated (AAV) vector and demonstrated induction of outer segments and improvement of photoreceptor function. Here we have extended our analysis and have demonstrated that the potential for ultrastructural improvement is dependent upon the age at which animals are treated, but the effect of a single injection on photoreceptor ultrastructure may be long-term. However, there was no significant effect on photoreceptor cell loss, irrespective of the date of administration, despite the improvements in morphology and function. Our investigation excluded procedure-related damage, vector toxicity and immune responses as major factors which might counteract the benefits of photoreceptor restoration, but suggested that transgene over-expression is of significance. These findings suggest that successful gene therapy in patients with photoreceptor defects may ultimately depend upon intervention in early stages of disease and upon accurate control of transgene expression.
视网膜变性慢（rds或Prph2(Rd2/Rd2)）小鼠是一种隐性视网膜色素变性模型，缺乏编码外周蛋白2的功能基因。这种膜糖蛋白是光感受器外节盘形成所必需的。rds小鼠的显著特征是完全无法发育出外节。我们之前使用腺相关（AAV）载体研究了基因替代疗法的短期效果，并证明了外节的诱导和光感受器功能的改善。在此，我们扩展了分析，证明超微结构改善的潜力取决于治疗动物的年龄，但单次注射对光感受器超微结构的影响可能是长期的。然而，尽管形态和功能有所改善，但无论给药日期如何，对光感受器细胞丢失均无显著影响。我们的研究排除了与操作相关的损伤、载体毒性和免疫反应作为可能抵消光感受器恢复益处的主要因素，但表明转基因过表达具有重要意义。这些发现表明，光感受器缺陷患者的成功基因治疗最终可能取决于疾病早期的干预以及转基因表达的精确控制。
