Optimization of treatment flow to improve performance of retinal gene therapy

优化治疗流程以提高视网膜基因治疗的效果

• 批准号: 399487171
• 负责人: Professor Dr. Mathias Seeliger
• 金额: --
• 依托单位: Arbeitsgruppe Neurodegeneration des Auges
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399487171?language=en
• 关键词: Optimization; treatment; flow; improve; performance

Gene therapy of the retina is a novel tool for the treatment of inherited retinal degenerations. Preclinical studies from several groups world-wide including our own clearly show the promise of this approach to provide a cure for this potentially blinding group of diseases. Following a relatively fast advancement from bench to bedside, several clinical studies have been started in the immediate past and further human trials are in preparation. While traditionally the focus in this field is on the expansion of therapeutic indications and vector development, opportunities for the optimization of treatment flow have at best received moderate attention. We believe, however, that quite substantial improvements in the efficacy and longevity of curative effects may be accomplished this way. A key, seminal part of the treatment is the subretinal injection. The general believe is that retina and RPE separate at the time of the injection and come together again after the bleb has resolved, which has been observed to take hours to a few days. However, there is to our best knowledge no comprehensive data on presumably influential parameters like best volume for injections, size of bleb/local pressure characteristics, and optimal time of day/conformance with circadian rhythm. In murine models, we have conducted preliminary studies in this regard using a standardized protocol developed over the past years. We found that the morphological ultrastructure at the subretinal injection site was much more compromised than previously thought. In particular, we found that subretinal injections regularly rupture photoreceptor outer segments instead of pulling them out of the retina/RPE interface. Based on our preliminary data, we further conducted a pilot study in an attempt to optimize the time point for injections. In particular, we aimed to take advantage of presumed mechanical fluctuations in RPE/retina bonds, which allegedly are minimal at the time of disc shedding. Indeed, we found that injections at the expected time of disc shedding produced considerable less damage than those 12h later. In this proposal, we explore options to improve the treatment procedure via an optimal synchronization with the circadian rhythm in order to achieve a superior outcome for a given therapy. Besides acute effects on morphology, we will study the long-term outcome in disease models for human inherited retinal degenerations, and assess whether the favorable effect observed is dependent on rod or cone vision. As the observation of photoreceptor disc shedding in the living human eye has recently been demonstrated, a circadian rhythm-synchronized treatment will certainly become possible soon in a clinical setting.

视网膜基因治疗是治疗遗传性视网膜变性的一种新方法。包括我们自己在内的全球多个研究小组的临床前研究清楚地表明，这种方法有望为这组潜在致盲疾病提供治疗方法。 随着从实验室到临床的相对快速的发展，几项临床研究已经开始，进一步的人体试验正在准备中。虽然传统上该领域的重点是扩大治疗适应症和载体开发，但优化治疗流程的机会充其量只得到适度的关注。然而，我们认为，可以通过这种方式实现疗效和疗效持久性的相当大的改进。视网膜下注射是治疗的关键和开创性部分。一般认为，视网膜和RPE在注射时分离，并在水泡消退后再次聚集在一起，据观察需要数小时至数天。然而，据我们所知，没有关于可能有影响的参数的综合数据，如最佳注射量、水泡大小/局部压力特征和一天中的最佳时间/与昼夜节律的一致性。在小鼠模型中，我们使用过去几年开发的标准化方案进行了这方面的初步研究。我们发现视网膜下注射部位的形态学超微结构比以前认为的要严重得多。特别是，我们发现视网膜下注射有规律地使感光细胞外段破裂，而不是将它们从视网膜/RPE界面拉出。基于我们的初步数据，我们进一步进行了初步研究，试图优化注射时间点。特别是，我们的目的是利用假定的机械波动的RPE/视网膜债券，这据称是最小的时候，光盘脱落。事实上，我们发现在预期的椎间盘脱落时间注射比12小时后注射产生的损伤要小得多。在这个建议中，我们探索通过与昼夜节律的最佳同步来改善治疗程序的选择，以便在给定的治疗中实现上级结果。除了对形态学的急性影响外，我们还将研究人类遗传性视网膜变性疾病模型的长期结果，并评估观察到的有利效果是否取决于视杆或视锥视力。由于在活体人眼中观察到感光盘脱落最近已被证明，昼夜节律同步治疗肯定会很快在临床环境中成为可能。