Activation of neuroprotective signalling pathways in the retina by aptamer

视网膜变性过程，如老年性黄斑变性(AMD)或视网膜色素变性(RP)，会导致光感受器死亡，从而导致失明。基于生长因子的治疗是一种经过实验验证的减缓或阻止光感受器退化的方法。脑源性神经营养因子是一种很有前途的神经营养生长因子，它通过激活TrκB信号通路发挥作用。通过使用已经发表的与TrκB受体特异性结合的适体，我们的目标是模拟BDNFB的神经保护作用，并开发更广泛适用的视网膜疾病治疗方法。同时，计划进一步研究和表征参与其中的单个信号分子的作用。我们的初步结果证实了TrκB适配子对原代视网膜细胞和视网膜器官模型的生物相容性。此外，在体外退变模型中表现出更好的结合效率和神经保护作用，用适配子激活TrκB受体特异性地靶向所需细胞，比实际配体更稳定，并且可以在更低的浓度下使用。本项目的目的是评价TrĸB适配子在治疗视网膜色素变性和黄斑变性等多因素视网膜变性疾病中的应用，同时更好地了解这些视网膜病变的潜在分子病理机制。

Retinal degeneration processes, such as those occurring in age-related macular degeneration (AMD) or retinitis pigmentosa (RP), result in the death of the photoreceptors and thus lead to blindness. Growth factor-based therapy is an experimentally proven approach to slow down or halt photoreceptor degeneration. A promising neurotrophic growth factor is the brain derived neurotrophic factor (BDNF), which unfolds its effect by activating the TrκB signal cascade. By using an already published aptamer that specifically binds to the TrκB receptor, we aim to mimic the neuroprotective effect of BDNF and develop more broadly applicable treatments for retinal diseases. At the same time, it is planned to further investigate and characterize the role of individual signaling molecules involved.Our preliminary results confirmed the biocompatibility of the TrκB aptamer on primary retinal cells and in the retinal organ model. In addition, a better binding efficiency and a neuroprotective effect were demonstrated in an ex vivo degeneration model.TrκB receptor activation with an aptamer targets specifically the desired cells, is more stable than the actual ligand, and can be used in much lower concentrations. This should reduce side effects and the problem of the low half-life time, which occurred in the previous BDNF therapy approaches.The aim of this project is to evaluate the therapeutic use of the TrĸB aptamer for the treatment of multifactorial retinal degenerative diseases of photoreceptor cells such as RP and AMD and at the same time to better understand the underlying molecular pathomechanisms of these retinopathies.