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含有可诱导保护机制并过表达脑源性神经营养因子（BDNF）的人类纹状体祖细胞可挽救亨廷顿病的表型。

Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington's disease phenotypes.

作者信息

Simmons Danielle A, Selvaraj Sridhar, Chen Tingshuo, Cao Gloria, Camelo Talita Souto, McHugh Tyne L M, Gonzalez Selena, Martin Renata M, Simanauskaite Juste, Uchida Nobuko, Porteus Matthew H, Longo Frank M

机构信息

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.

出版信息

Mol Ther Methods Clin Dev. 2025 Jan 22;33(1):101415. doi: 10.1016/j.omtm.2025.101415. eCollection 2025 Mar 13.

DOI:10.1016/j.omtm.2025.101415
PMID:39995448
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11848452/
Abstract

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.

摘要

亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其特征为纹状体萎缩。由于神经营养因子（NTs），主要是脑源性神经营养因子（BDNF）的纹状体水平降低而导致的营养支持减少，在HD发病机制中起重要作用；恢复NTs具有显著的治疗潜力。人类多能干细胞（hPSCs）为NTs递送提供了一个可扩展的平台，但存在包括畸胎瘤形成在内的潜在安全风险。我们对hPSCs进行基因改造，使其组成性地产生BDNF，并包含诱导性保障措施，以便在出现安全问题时消除这些细胞。本研究检测了源自这些hPSCs的纹状体祖细胞（STRpcs）脑内注射移植对R6/2小鼠HD表型的疗效。移植的过表达BDNF的STRpcs减轻了运动和认知缺陷，并减少了突变型亨廷顿蛋白聚集体。用雷帕霉素激活诱导性安全开关可安全地消除移植细胞。这些结果表明，通过一个包含安全开关的新型基于hPSC的平台递送BDNF可能是一种安全有效的HD治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/80b29fea028f/gr8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/21caf50d5bfb/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/dd892ae9dc69/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/59e68f9600b5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/861fbc1653b0/gr3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/58d81367ad49/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ae/11848452/fa2d3bf3669c/gr6.jpg
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本文引用的文献

1
Therapeutic advances in neural regeneration for Huntington's disease.亨廷顿舞蹈症神经再生的治疗进展
Neural Regen Res. 2024 Sep 1;19(9):1991-1997. doi: 10.4103/1673-5374.390969. Epub 2023 Dec 15.
2
Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.移植的人类神经干细胞可挽救zQ175亨廷顿舞蹈症小鼠的表型并支配纹状体。
Mol Ther. 2023 Dec 6;31(12):3545-3563. doi: 10.1016/j.ymthe.2023.10.003. Epub 2023 Oct 7.
3
Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington's Disease.
TrkB和TrkC受体信号的药理学协同激活可改善亨廷顿舞蹈病小鼠模型中的纹状体神经病理学和运动缺陷。
J Huntingtons Dis. 2023;12(3):215-239. doi: 10.3233/JHD-230589.
4
Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics.脑源性神经营养因子失调作为亨廷顿舞蹈病的关键病理特征：机制与潜在疗法
Biomedicines. 2023 Aug 16;11(8):2275. doi: 10.3390/biomedicines11082275.
5
High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition.利用 DNA-PKcs 抑制实现人原代细胞中同源定向修复的高效转基因整合。
Nat Biotechnol. 2024 May;42(5):731-744. doi: 10.1038/s41587-023-01888-4. Epub 2023 Aug 3.
6
Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis.间充质干细胞治疗亨廷顿病：一项荟萃分析
Stem Cells Int. 2023 Apr 30;2023:1109967. doi: 10.1155/2023/1109967. eCollection 2023.
7
Clinical trials using dental stem cells: 2022 update.使用牙干细胞的临床试验：2022年更新
World J Stem Cells. 2023 Mar 26;15(3):31-51. doi: 10.4252/wjsc.v15.i3.31.
8
Molecular Pathophysiological Mechanisms in Huntington's Disease.亨廷顿舞蹈症的分子病理生理机制
Biomedicines. 2022 Jun 17;10(6):1432. doi: 10.3390/biomedicines10061432.
9
Restoration of BDNF, DARPP32, and D2R Expression Following Intravenous Infusion of Human Immature Dental Pulp Stem Cells in Huntington's Disease 3-NP Rat Model.静脉输注人未成熟牙髓干细胞后亨廷顿病 3-NP 大鼠模型中 BDNF、DARPP32 和 D2R 表达的恢复。
Cells. 2022 May 17;11(10):1664. doi: 10.3390/cells11101664.
10
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Brain. 2022 Jun 3;145(5):1584-1597. doi: 10.1093/brain/awac086.