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神经元类型特定的表观基因组编辑来降低SNCA表达:在同核蛋白病变中对精准医学的影响

Zhiguo Sun¹, Boris Kantor², Ornit Chiba-Falek^3,4

¹CLAIRIgene, LLC, Durham, NC 27701, USA.

Molecular therapy. Nucleic acids

|December 22, 2023

概括

我们开发了一种新型基因疗法,针对SNCA过度表达在帕金森病 (PD) 和患有勒维体 (DLB) 的痴呆症. 这种表观基因组疗法显示出有望通过专门减少受影响神经元中的SNCA来治疗同核蛋白病变.

科学领域:

神经科学是一个神经科学.
遗传学遗传学是一种遗传学.
分子生物学分子生物学

背景情况:

过度表达SNCA基因是像帕金森病 (PD) 和患有勒维体 (DLB) 的痴呆症等同核蛋白病变的核心.
尽管有共同的相似之处,PD和DLB表现出明显的病理特征,需要有针对性的治疗方法.
目前针对同核蛋白病变的治疗方法主要是治疗症状,这凸显了对疾病修饰疗法的需要.

研究的目的:

设计一种针对神经元类型的特异性表观基因组疗法,针对SNCA针对同核蛋白病变.
为了在涉及PD和DLB的多巴胺和胆固醇神经元中实现SNCA的精确下调.
在人类诱导多能干细胞 (hiPSC) 衍生神经元模型中验证该系统的治疗潜力.

主要方法:

使用CRISPR-dSaCas9和针对SNCA内核1的导向RNA (gRNA) 开发一个全集的隐形病毒载体系统.
将CRISPR系统与KRAB/MeCp2转录抑制域 (TRD) 融合以实现基因沉默.
利用神经元类型特定的促进剂 (TH用于多巴胺基神经元,ChAT用于胆固醇神经元) 来驱动治疗系统.

主要成果:

在患有SNCA三倍化患者的hiPSC衍生神经元中,SNCA mRNA和蛋白质的有效和特定下调.
拯救与疾病相关的细胞表型,包括减少Ser129-酸化α-synuclein,改善神经元活力和纠正线粒体功能障碍.
在体外成功证明了一种新的神经元特异性SNCA向的表观基因组疗法.

结论:

一种针对SNCA过度表达的新型神经元类型特异性表观基因组疗法已成功开发.
该系统显示了治疗PD和DLB等同核蛋白病变的巨大潜力.
这项研究为进一步的临床前开发和最终的临床试验提供了坚实的基础.

关键词:

DLB DLB 的意思是DLB 的意思 MT:编辑RNA/DNA的方法警方警方警方警方帕金森病是帕金森氏症的一种疾病.这是SNCA的SNCA.这是一种α-synuclein.胆固醇神经元是一种神经元.患有利维体痴呆症的痴呆症多巴胺类神经元的神经元编辑表观遗传学编辑基因治疗的基因疗法这是 hiPSC.人类诱导的多能干细胞干细胞.隐形病毒载体隐形病毒载体合成核蛋白病变 (synucleinopathies) 是一种同核蛋白病变.

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