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针对47型遗传性性的AP4B1基因替代疗法的临床前开发

Jessica P Wiseman^1,2, Joseph M Scarrott^1,3, João Alves-Cruzeiro¹

¹Sheffield Institute for Translational Neuroscience (SITraN), Division of Neuroscience, University of Sheffield, Sheffield, UK.

EMBO molecular medicine

|October 2, 2024

概括

使用AAV9/hAP4B1的基因疗法通过恢复AP4B1蛋白在小鼠中成功治疗了性残47 (SPG47). 这种方法对SPG47患者的未来临床试验有希望.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
基因治疗基因治疗

背景情况:

性四肢47 (SPG47) 是一种由AP4B1基因突变引起的遗传神经疾病,导致AP-4复合体缺陷.
SPG47呈现出渐进的性,发育迟缓,智力障碍和.

研究的目的:

通过恢复功能AP4B1蛋白水平来评估SPG47的基因疗法的治疗潜力.
在SPG47小鼠模型中评估AAV9介导的hAP4B1基因传递的有效性和安全性.

主要方法:

表达人类AP4B1 (AAV9/hAP4B1) 的腺相关病毒血清型9被输送到SPG47小鼠的大中.
评估了基因转移,恢复AP-4载荷 (ATG9A),减少神经病理标记 (calbindin球体),大脑解剖学,运动功能和血NfL水平.
进行的IND启用研究,包括免疫性和非人类灵长类动物 (NHP) 毒理学和生物分布研究.

主要成果:

在小鼠中,一次AAV9/hAP4B1的使用导致了广泛的基因转移,并改善了SPG47的特征.
关键的改善包括纠正ATG9A定位,减少球形状,正常化大脑结构,改善运动功能和恢复血NfL水平.
国家健康计划研究表明安全性和有利的生物分布,没有显著的不良事件.

结论:

AAV9/hAP4B1基因疗法是SPG47的一个有前途的治疗策略,在临床前模型中证明了有效性和安全性.
这些发现为在SPG47患者中进行临床试验的研究新药 (IND) 申请提供了坚实的基础.

关键词:

在 AAV AAV AAV 中.在 AP4B1 中,AP4B1 是基因治疗基因治疗在HSP的基础上,HSP是HSP.在SPG47中,SPG47就是SPG47.

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