Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis

阿尔茨海默病(AD)是一种破坏性的与年龄相关的神经退行性疾病，影响5.6 数百万65岁及以上的美国人。预计65岁及以上的美国阿尔茨海默病患者人数将达到 到2050年达到1380万。尽管美国食品和药物管理局(FDA)已经批准了五种药物 对于阿尔茨海默病，没有一个人可以减缓或阻止导致神经元损伤和破坏的过程 阿尔茨海默病症状。因此，迫切需要更好地了解AD并开发新的治疗方法。 一般认为，饮酒会影响阿尔茨海默病的风险。然而，该协会 酒精和阿尔茨海默病之间的关系非常复杂，结论仍然存在争议。因此，更多 对酒精和阿尔茨海默病之间的联系进行调查是非常必要的。 由于血脑屏障(BBB)，大脑传统上被认为是免疫特权的。 以及大脑中缺乏淋巴管。然而，最近的研究产生了令人信服的数据 修改这一概念。大脑并不是完全免疫特权，但具有免疫活性。 特别是，PD-1/PD-L1通路在神经退行性疾病中引起了极大的关注， 包括阿尔茨海默病和肌萎缩侧索硬化。抗PD-1和抗PD-L1单抗均显示有效 在逆转阿尔茨海默病转基因小鼠模型中的认知障碍和减少疾病病理 和tau驱动的疾病模型。阻断PD-1/PD-L1通路被认为可以恢复 免疫系统和大脑之间的免疫通讯。尽管如此，函数 PD-1/PD-L1在AD发病机制中的作用尚不完全清楚。此外，抗PD-1或抗PD-L1 单抗不能通过血脑屏障。因此，非常有必要研究是否很小 抗PD-L1抑制剂可能通过血脑屏障，其作用与抗体不同。 该项目的目标是：1)使用已建立的大鼠酒精中毒模型来评估 饮酒改变了大脑中的免疫细胞图谱；2)调查 5XFAD转基因小鼠脑内应用抗PD-L1抑制剂可帮助对抗AD。 我们已经建立了一种大鼠酒精中毒模型来研究酒精性肝纤维化。我们会 使用相同的模型来研究酒精和大脑中免疫细胞图谱之间的关联。 我们已经开发了小分子抗PD-L1抑制剂，可以有效地阻断PD-L1/PD-1的相互作用。因为 由于体型较小，它们将有更好的机会越过BBB。我们最近开发了一种BBB- 转位多肽。我们将把这种多肽与抗PD-L1抑制剂偶联，以增加它们的递送 大脑。该项目的成功完成将为如何通过以下方式对抗AD提供更多的见解 调节大脑中的免疫细胞图谱。

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder that affects 5.6 million Americans age 65 and older. The number of Americans age 65 and older with AD is projected to reach 13.8 million by 2050. Although the Food and Drug Administration (FDA) has approved five drugs for AD, no one of them can slow or stop the damage and destruction of neurons that causing the symptoms of AD. Therefore, there is an urgent need to better understand AD and develop novel therapies. It is generally believed that alcohol consumption affects the risk of AD. However, the association between alcohol and AD is very complex, and the conclusions are still controversial. As a result, more investigations into the association between alcohol and AD are highly needed. The brain was traditionally considered immune-privileged because of the blood-brain barrier (BBB) and the lack of lymphatic vessels in the brain. However, recent studies have generated compelling data to revise this concept. The brain is not completely immune-privileged but is immunocompetent. Particularly, the PD-1/PD-L1 pathway has attracted much attention in neurodegenerative diseases, including AD and ALS. Both anti-PD-1 and anti-PD-L1 monoclonal antibodies have shown effectiveness in reversing cognitive impairments and reducing disease pathology in a transgenic mouse model of AD and a tau-driven disease model. The blockade of the PD-1/PD-L1 pathway is believed to restore the immunological communication between the immune system and the brain. Nevertheless, the function of PD-1/PD-L1 in the pathology of AD is not fully understood. Moreover, the anti-PD-1 or anti-Pd-L1 monoclonal antibodies cannot cross the BBB. It is, therefore, highly necessary to study whether small anti-PD-L1 inhibitors, which may cross the BBB, have different effects than the antibodies. The objectives of the project are:1) Using an established rat alcoholism model to evaluate whether alcohol consumption changes the immune cell profiles in the brain; 2) Investigate whether delivery of small anti-PD-L1 inhibitors to the brain of 5XFAD transgenic mice can help combat AD. We have developed a rat alcoholism model to study alcoholic liver fibrosis in the parent grant. We will use the same model to investigate the association between alcohol and immune cell profiles in the brain. We have developed small anti-PD-L1 inhibitors that efficiently block the PD-L1/PD-1 interaction. Because of their small size, they will have better chance to cross the BBB. We recently developed a BBB- translocating peptide. We will conjugate this peptide to anti-PD-L1 inhibitors to increase their delivery to the brain. Successful accomplishment of the project will provide more insights on how to combat AD by regulating the immune cell profiles in the brain.