Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Stem Cell Reports. 2018 Jun 5;10(6):1696-1704. doi: 10.1016/j.stemcr.2018.03.024. Epub 2018 Apr 26.
Trophic factor delivery to the brain using stem cell-derived neural progenitors is a powerful way to bypass the blood-brain barrier. Protection of diseased neurons using this technology is a promising therapy for neurodegenerative diseases. Glial cell line-derived neurotrophic factor (GDNF) has provided benefits to Parkinsonian patients and is being used in a clinical trial for amyotrophic lateral sclerosis. However, chronic trophic factor delivery prohibits dose adjustment or cessation if side effects develop. To address this, we engineered a doxycycline-regulated vector, allowing inducible and reversible expression of a therapeutic molecule. Human induced pluripotent stem cell (iPSC)-derived neural progenitors were stably transfected with the vector and transplanted into the adult mouse brain. Doxycycline can penetrate the graft, with addition and withdrawal providing inducible and reversible GDNF expression in vivo, over multiple cycles. Our findings provide proof of concept for combining gene and stem cell therapy for effective modulation of ectopic protein expression in transplanted cells.
使用干细胞衍生的神经祖细胞向大脑输送营养因子是一种绕过血脑屏障的有效方法。利用这项技术保护患病神经元是治疗神经退行性疾病的一种很有前途的疗法。胶质细胞源性神经营养因子 (GDNF) 已使帕金森病患者受益，并正在进行肌萎缩侧索硬化症的临床试验。然而，慢性营养因子输送如果出现副作用，则无法进行剂量调整或停止。为了解决这个问题，我们设计了一种强力霉素调控载体，允许治疗分子的诱导和可逆表达。通过稳定转染载体，将人诱导多能干细胞 (iPSC) 衍生的神经祖细胞移植到成年小鼠大脑中。强力霉素可以穿透移植物，通过添加和撤回在体内提供多个循环的诱导和可逆的 GDNF 表达。我们的研究结果为基因和干细胞治疗相结合提供了概念验证，可有效调节移植细胞中异位蛋白的表达。
