Kobinger Gary P, Louboutin Jean-Pierre, Barton Elisabeth R, Sweeney H Lee, Wilson James M
Gene Therapy Program, Division of Medical Genetics, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
Hum Gene Ther. 2003 Oct 10;14(15):1441-9. doi: 10.1089/104303403769211655.
Successful gene therapy for most inherited diseases will require stable expression of the therapeutic gene. This can be addressed with integrating or self-replicating viruses by targeting postmitotic cells that have a long lifetime or stem cells that can replenish defective tissue with corrected cells. In this study, we explore the possibility of targeting a muscle stem cell population in situ through in vivo administration of vector. To develop this concept, we selected a mouse model of muscular dystrophy (mdx mice) that undergoes rapid turnover of muscle fibers. In vivo targeting of muscle progenitor cells, notably satellite cells, with a pseudotyped lentiviral vector encoding the minidystrophin restores dystrophin expression and provides functional correction in skeletal muscle of mdx mice. This study shows that progenitor cells can be genetically engineered in vivo and subsequently proliferate into terminally differentiated tissue carrying the genetic graft in a way that stably corrects function.
对于大多数遗传性疾病而言，成功的基因治疗需要治疗性基因的稳定表达。这可以通过整合型或自我复制型病毒来实现，方法是靶向寿命较长的有丝分裂后细胞或能够用校正后的细胞补充缺陷组织的干细胞。在本研究中，我们探索了通过体内注射载体原位靶向肌肉干细胞群体的可能性。为了拓展这一概念，我们选择了一种肌肉纤维快速更新的肌营养不良小鼠模型（mdx小鼠）。用编码小肌营养不良蛋白的假型慢病毒载体在体内靶向肌肉祖细胞，尤其是卫星细胞，可恢复mdx小鼠骨骼肌中肌营养不良蛋白的表达并提供功能校正。这项研究表明，祖细胞可以在体内进行基因工程改造，随后增殖进入携带基因移植的终末分化组织，从而稳定地校正功能。
