Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.

中文翻译：

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AP4B1 基因替代疗法治疗遗传性痉挛性截瘫 47 型的临床前开发。


痉挛性截瘫 47 （SPG47） 是一种由衔接蛋白复合物 4 β1 亚基 （AP4B1） 基因突变引起的神经系统疾病，导致 AP-4 复合物缺陷。SPG47 的特征是进行性痉挛性截瘫、全面发育迟缓、智力障碍和癫痫。旨在恢复功能性 AP4B1 蛋白水平的基因治疗是改善疾病表型的合理治疗策略。在这里，我们报道了表达 hAP4B1 （AAV9/hAP4B1） 的腺相关病毒血清型 9 单次递送到大脑池中，导致广泛的基因转移和各种疾病标志物的恢复，包括 AP-4 货物 （ATG9A） 错误定位、小脑深部核中的钙结合蛋白阳性球体、解剖脑缺陷和运动功能障碍，在 SPG47 小鼠模型中。此外，基于 AAV9/hAP4B1 的基因疗法表明，治疗小鼠的血浆神经丝光 （NfL） 水平恢复。在这些临床前概念验证数据的鼓励下，我们进行了 IND 支持研究，包括免疫原性和 GLP 非人灵长类动物 （NHP） 毒理学研究。重要的是，NHP 安全性和生物分布研究显示没有与治疗干预相关的显着不良事件。这些发现为治疗效果和安全性提供了证据，为寻求针对 SPG47 患者的临床试验的 IND 申请奠定了坚实的基础。