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

阿尔茨海默病（AD）是一种毁灭性的与年龄相关的神经退行性疾病，影响5.6万人

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.