An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model.
An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model.
复制标题
DOI：
10.15252/emmm.202215968
复制
发表时间：
2023-04-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
造血干细胞和祖细胞（HSPC）可以在适当骨髓清除宿主的中枢神经系统中建立持久的小胶质细胞样后代。我们利用这种方法来治疗严重的CLN 1神经退行性疾病，这是由于棕榈酰蛋白硫酯酶-1（PPT 1）缺乏引起的神经元蜡样脂褐质沉积症的最具侵袭性形式。我们在这里提供了第一个证据，即（i）野生型HSPC的移植发挥了CLN 1症状的部分但持久的缓解;（ii）通过慢病毒基因转移过度表达hPPT 1的HSPC的移植增强了HSPC移植的治疗益处，首次证明了对于纯神经退行性疾病如CLN 1疾病的这种剂量效应益处;（iii）通过新的脑室内（ICV）方法移植过表达hPPT 1的HSPC足以在没有转导细胞的造血组织移植的情况下短暂改善CLN 1症状;和（iv）转导的HSPC静脉内和ICV的组合移植产生强有力的治疗益处，特别是对有症状的动物。总的来说，这些发现提供了这种新方法治疗CLN 1疾病和可能的其他神经退行性疾病的有效性和可行性的第一个证据，为其未来的临床应用铺平了道路。CLN 1疾病是由棕榈酰蛋白硫酯酶1（PPT 1）缺乏引起的。这是最具侵略性的儿童神经退行性疾病之一，医疗需求未得到满足。在这篇手稿中，我们提供了第一个证据，证明了一种基于造血干细胞（HSC）的基因治疗新方法在CLN 1小鼠模型中的疗效。
Hematopoietic stem and progenitor cells (HSPCs) can establish a long‐lasting microglia‐like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoyl‐protein thioesterase‐1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild‐type HSPCs exerts partial but long‐lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over‐expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose–effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over‐expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1‐symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application. CLN1 disease is caused by a deficiency of palmitoyl‐protein thioesterase 1 (PPT1). This is one of the most aggressive childhood neurodegenerative diseases with unmet medical needs. In this manuscript, we provide first evidence of the efficacy of a novel approach of hematopoietic stem cell (HSC)‐based gene therapy in the CLN1 mouse model.
登录
查看更多内容
DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
DOI：
10.1016/j.bbadis.2013.05.026
发表时间：
2013-11
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Hawkins-Salsbury JA;Cooper JD;Sands MS
通讯作者：
Sands MS
影响因子：
3.8
作者：
Hu, Jie;Lu, Jui-Yun;Hofmann, Sandra L.
通讯作者：
Hofmann, Sandra L.
DOI：
10.1073/pnas.251485198
发表时间：
2001-11-20
影响因子：
11.1
作者：
Gupta, P;Soyombo, AA;Hofmann, SL
通讯作者：
Hofmann, SL
DOI：
10.1002/ajmg.1320570253
发表时间：
1995-06-05
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
LAKE, BD;HENDERSON, DC;VELLODI, A
通讯作者：
VELLODI, A