中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (5): 702-705.doi: 10.4103/1673-5374.182682

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

利用基因工程骨髓间充质干细胞移植治疗成年和少年亨廷顿氏病的临床试验

  

  • 收稿日期:2016-04-15 出版日期:2016-05-20 发布日期:2016-05-20

Clinical trial perspective for adult and juvenile Huntington’s disease using genetically-engineered mesenchymal stem cells

Peter Deng, Audrey Torrest, Kari Pollock, Heather Dahlenburg, Geralyn Annett, Jan A. Nolta, Kyle D. Fink*   

  1. Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, CA, USA
  • Received:2016-04-15 Online:2016-05-20 Published:2016-05-20
  • Contact: Kyle D. Fink, Ph.D., kdfink@ucdavis.edu.
  • Supported by:

    Support for this project was provided by a NIH NIGMS Predoctoral Fellowship T32GM099608 (Deng), NIH NRSA Postdoctoral Fellowship F32NS090722 (Fink), a NIH Director’s transformative award 1R01GM099688 (Nolta), A Stewart’s and Dake Family Gift (Fink), California Institute for Regenerative Medicine (CIRM) DR2-05415 (Wheelock/Nolta), and philanthropic donors from the HD community, including the Roberson family and Team KJ.

摘要:

美国加州大学戴维斯分校再生疗法研究所已经在转基因亨廷顿氏病小鼠模型中测试了基因工程人骨髓间充质干的安全性和有效性。使用FK506 /雷帕霉素对亨廷顿氏病小鼠进行免疫抑制以避免异种免疫应答并允许长达28天的植入后观察期,这与NSG免疫缺陷小鼠植入结果类似。考虑到各种神经退行性疾病临床试验中间充质干细胞已得到越来越多的支持,以及Jan A. Nolta教授研究所的临床前和体内生物安全数据,结合当前缺乏可用的亨廷顿氏病治疗方法,Jan A. Nolta教授认为,间充质干细胞是亨廷顿氏病治疗中的领跑者。亨廷顿氏病是一种由扩展多聚谷氨酰胺道导致神经元进行性变性的常染色体显性遗传疾病,主要病理症状发生在壳核,尾状核和大脑皮层。据报道,亨廷顿氏病患者由于突变亨廷顿蛋白抑制了转录水平,因而脑源性神经营养因子水平较低。而恢复脑源性神经营养因子水平被证明具有促存活效应,并可改善转基因亨廷顿氏病模型的症状。因此,脑源性神经营养因子被认为是治疗亨廷顿氏病神经元功能障碍的总候选人。现在,利用干细胞疗法对神经退行性疾病的治疗越来越有吸引力。其具有与内源性微环境协同作用的能力,通过营养因子分泌上调固有细胞增殖或神经保护能力可能会提高移植组织的整体再生潜能。间充质干细胞尤其已经由于其独特的生物性质在再生医学和免疫学中大放异彩。间充质干细胞是从成人组织可随时接触到的广泛子集派生多能干细胞。间充质干细胞能够分泌神经营养因子并响应于局部炎症元素,增强神经发生和突触发生,并抑制凋亡信号。由于其免疫调节的潜能,间充质干细胞在同种异体移植后不需要免疫抑制,这些情况都已经证明其在临床试验中强有力的安全形象。

orcid: 0000-0002-0235-5038(Kyle D. Fink)

Abstract:

"Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells (MSC) to secrete brain-derived neurotrophic factor (BDNF) supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington’s disease (HD). There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer’s disease, and some forms of Parkinson’s disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system."

Key words: mesenchymal stem cells, neurodegenerative disorders, Huntington’s disease, genetic engineering, brain derived neurotrophic factor