Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease
Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease
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DOI：
10.1073/pnas.1509914112
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发表时间：
2015-10-27
影响因子：
11.1
通讯作者：
Aguirre, Gustavo D.
中科院分区：
文献类型：
--
作者：
Beltran, William A.;Cideciyan, Artur V.;Aguirre, Gustavo D.
遗传性视网膜变性导致感光神经元的进行性丧失，最终导致失明。正在开发的矫正或神经保护基因疗法可以在变性前阶段提供，以防止疾病的发作，以及在中期变性阶段，以减缓进展速度。迄今为止，大多数临床前基因治疗的成功都是作为变性前干预措施。在许多动物模型中，以及在人类研究中，迄今为止，在变性开始后很好地施用视网膜基因治疗，即使在成功逆转功能障碍时，也不能改变进展速度。我们评估了由视网膜色素变性GT3调节因子（RPGR）基因突变引起的X连锁视网膜色素变性（XLRP）犬模型中疾病中间阶段基因治疗的结果。时空疾病的自然史的定义和治疗剂量的基础上predegeneration的结果进行选择。然后在中期疾病的早期和晚期进行干预，并通过非侵入性成像，电生理功能和视觉行为监测感光细胞变性超过2年。所有参数均显示，治疗后疾病的进展时间进程基本上得到显著抑制，与对照眼相比，这导致视网膜功能和视觉行为长期改善。组织学证实，人RPGR转基因在光感受器中稳定表达，并与视杆细胞、视锥细胞和ON双极细胞的结构保存改善以及视蛋白错误定位的校正相关。在临床相关的大型动物模型中的这些发现证明了RPGR基因扩增的长期疗效，并大大拓宽了RPGR-XLRP患者的干预治疗窗口。
Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.