由于血脑屏障的药物限制性使得许多中枢神经系统疾病难以完全治愈。目前基因治疗已发展成为治疗中枢神经系统疾病的新策略。腺相关病毒（AAV）凭借自身特性被认为是治疗该类疾病的理想基因载体。然而临床试验中发现，现有的AAV穿过血脑屏障效率并没有达到预期，不能有效发挥治疗作用。申请人根据“CREATE”理论，改建现有AAV并在多品系小鼠和灵长类动物上进行验证，最终得到一个可跨种系、高效靶向中枢神经系统的新型AAV-CPP.16基因载体。该载体穿越血脑屏障效率远远超过当前现有AAV。为实现将科研向实际应用的转化，本项目将通过：明确AAV-CPP.16在血脑屏障中的特异性受体；利用新一代血脑屏障体3D外模型预判该载体在人体内穿越血脑屏障效率；以及评价该载体在治疗以脊髓性肌肉萎缩症为例的中枢神经系统疾病模型上的效果，对AAV-CPP.16的临床应用价值进行判断，为该载体进一步走向临床试验提供理论依据。

Many central nervous system diseases are difficult to be completely cured because of the drug limitations of the blood-brain barrier.Gene therapy has been developed as a new strategy for the treatment of central nervous system diseases. Adeno-associated virus (AAV) with its own characteristics is considered as an ideal gene vector for the treatment of central nervous system disease among all kinds of vectors. In practice, however, existing AAV has been found to be far less efficient than expected in crossing the blood-brain barrier. Based on "CREATE" theory, through continuous attempts to modify the existing AAV and screening in multi-strain mice and primates, the applicant has finally obtained a novel and highly efficient AAV-CPP.16 gene vector that can cross species lines and target the central nervous system. AAV-CPP.16 not only has a high scientific value, but also has a promising clinical application potential. In order to further improve the experimental content and finally achieve the goal of the transformation from scientific research to practical application, this project will go through with the identification of the specific receptor of AAV-CPP.16, using the Blood-brain-barrier organoids to predict of the efficiency of AAV-CPP.16 in crossing the blood-brain barrier in human body and, moreover, evaluating AAV-CPP.16 as the vector to carry the therapeutic gene for practical application effect in the treatment of mouse spinal muscular atrophy disease model. Finally, with these methods we’ll explore the clinical application value of AAV-CPP.16.