Neuronal-type-specific epigenome editing to decrease SNCA expression: Implications for precision medicine in synucleinopathies.
Neuronal-type-specific epigenome editing to decrease SNCA expression: Implications for precision medicine in synucleinopathies.
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DOI：
10.1016/j.omtn.2023.102084
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发表时间：
2024-03-12
期刊：
影响因子：
--
通讯作者：
Chiba-Falek, Ornit
中科院分区：
文献类型：
--
作者：
Sun, Zhiguo;Kantor, Boris;Chiba-Falek, Ornit
SNCA的过表达与突触核蛋白病的发病机制有关，特别是帕金森病（PD）和路易体痴呆（DLB）。虽然PD和DLB在临床和病理上有一些相似之处，但每种疾病都有不同的特征，包括主要受影响的大脑区域和神经元类型。我们的目标是开发神经元型特异性snca靶向的突触核蛋白病表观基因组疗法。该系统基于一种由CRISPR-dSaCas9和靶向SNCA内含子1的引导RNA （gRNA）组成的一体化慢病毒载体，融合了kr<s:1> pel-associated box (KRAB)/甲基CpG结合蛋白2 （MeCp2）转录抑制域（TRD）的合成抑制分子。为了实现对多巴胺能神经元和胆碱能神经元的神经元类型特异性，该系统分别由酪氨酸羟化酶（TH）和胆碱乙酰转移酶（ChAT）启动子驱动。将该系统导入人诱导多能干细胞（hiPSC）衍生的SNCA三倍复制患者的多巴胺能和胆碱能神经元，可导致SNCA mrna和蛋白质的有效和神经元类型特异性下调。此外，grna - dsacas9抑制系统的SNCA水平降低挽救了疾病相关的细胞表型，包括ser129磷酸化的α-突触核蛋白、神经元活力和线粒体功能障碍。我们建立了一种新的神经元类型特异性snca靶向表观基因组疗法，并使用基于人类疾病模型提供了概念的体外证明。我们的研究结果支持了我们的系统对PD和DLB的治疗潜力，并为进一步的临床前动物模型研究提供了基础，以研究新药（IND）的启用和临床试验。Chiba-Falek及其同事开发了一种新的神经元类型特异性snca靶向表观基因组治疗平台。该平台在多巴胺能神经元和胆碱能神经元中特异性表达，分别在帕金森病和路易体痴呆中受到影响。利用人类ipsc -疾病模型证明了该平台在拯救疾病相关扰动方面的功效。
Overexpression of SNCA has been implicated in the pathogenesis of synucleinopathies, particularly Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). While PD and DLB share some clinical and pathological similarities, each disease presents distinct characteristics, including the primary affected brain region and neuronal type. We aimed to develop neuronal-type-specific SNCA-targeted epigenome therapies for synucleinopathies. The system is based on an all-in-one lentiviral vector comprised of CRISPR-dSaCas9 and guide RNA (gRNA) targeted at SNCA intron 1 fused with a synthetic repressor molecule of Krüppel-associated box (KRAB)/ methyl CpG binding protein 2 (MeCp2) transcription repression domain (TRD). To achieve neuronal-type specificity for dopaminergic and cholinergic neurons, the system was driven by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) promoters, respectively. Delivering the system into human induced pluripotent stem cell (hiPSC)-derived dopaminergic and cholinergic neurons from a patient with the SNCA triplication resulted in efficient and neuronal-type-specific downregulation of SNCA-mRNA and protein. Furthermore, the reduction in SNCA levels by the gRNA-dSaCas9-repressor system rescued disease-related cellular phenotypes including Ser129-phophorylated α-synuclein, neuronal viability, and mitochondrial dysfunction. We established a novel neuronal-type-specific SNCA-targeted epigenome therapy and provided in vitro proof of concept using human-based disease models. Our results support the therapeutic potential of our system for PD and DLB and provide the foundation for further preclinical studies in animal models toward investigational new drug (IND) enablement and clinical trials. Chiba-Falek and colleagues have developed a novel neuronal-type-specific SNCA-targeted epigenome therapy platform. This platform is expressed specifically in dopaminergic and cholinergic neurons, which are affected in Parkinson’s and dementia with Lewy bodies, respectively. The efficacy of the platform in rescuing disease-related perturbations was demonstrated using human iPSC-disease models.
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影响因子：
3.7
作者：
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