酶替代疗法（ERT）是治疗溶酶体疾病（LSD）最有效的方法。 血脑屏障(BBB)严重阻碍药物入脑， 限制了ERT在含中枢神经系统（CNS）病变的LSD中的应用。 目前已有的跨越BBB的方法其缺陷在于药物入脑量很低且无明显疗效如延长疾病小鼠平均寿命。 研究表明一新型多肽载体(K16ApoE)在一LSD疾病小鼠模型中， 通过与三肽基肽酶I非共价结合可大量将药物输送入脑且小鼠寿命显著延长。 然而K16ApoE的作用机制不清限制了其临床转化的可能性。因此，本项目将从K16ApoE的药代动力学机制及其入脑途径， K16ApoE与药物以及BBB的相互作用对该多肽的作用机理展开深入研究。 在阐明K16ApoE作用机制的基础上进一步对序列进行优化， 同时建立药代动力学生物仿真模型优化注射指数。为未来动物体内的长期功效研究提供重要支持。本项目的结果对LSD乃至CNS疾病的治疗具有变革性意义。

The enzyme replacement therapy (ERT) has been proved to be the most effective way for lysosomal storage disorder (LSD) treatment. However, the blood-brain barrier (BBB) presents a major challenge to deliver therapeutics in central nervous system (CNS), which limits the application of ERT in CNS-involved LSD. Methods do exist to help recombinant lysosomal protein therapeutics cross the BBB in animal models but results have been modest in terms of low levels achievable in the brain and therapeutic value in terms of increasing the life-span of animal models remains to be demonstrated in a convincing way. We recently reported an efficacy study on a novel in-trans peptide carrier (K16ApoE) in late-infantile neuronal ceroid lipofuscinosis (LINCL) mouse model. Results demonstrated that supraphysiological levels of TPP1 were achieved in the brain after co-injection of TPP1 and K16ApoE mixture. Importantly, peptide-mediated delivery of TPP1 from the bloodstream into the brain translates into significantly increased lifespan. However, the mechanism of action of K16ApoE is yet to be definitively elucidated which greatly limits its clinical translational potential. Here, we propose this study to dissect the mechanism of K16ApoE mediated drug delivery across BBB. Specifically, we will explore the pharmacokinetics mechanism of K16ApoE, the route and distribution of K16ApoE from blood to brain, the specificity of the therapeutics delivered by K16ApoE and the interaction between K16ApoE and BBB. Based on the characterization of mechanism, we will further optimize the sequence of K16ApoE to screen for the candidate with optimal therapeutic index. Meanwhile, the computer simulation model for K16ApoE pharmacokinetics will be developed to compute the best injection parameters, which will then be testified in in vivo model. The study will lay the foundation for the long-term efficacy study in preclinical animal models. Overall, success in these studies will be a major breakthrough, changing the way we think about therapy for CNS disorders.