Use of Mesenchymal Stem Cells to Enhance the Efficacy of Gene Therapy
Use of Mesenchymal Stem Cells to Enhance the Efficacy of Gene Therapy
复制标题
利用间充质干细胞增强基因治疗的功效
DOI：
10.1007/978-1-0716-2772-3_19
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Takashi Okada
中科院分区：
文献类型：
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作者：
Hiromi Hayashita-Kinoh;Takashi Okada
本文中，提供了一种使用间充质干细胞（MSC）调节犬杜氏肌营养不良症（DMD）模型中针对rAAV转导的免疫应答的方法。目的是克服针对腺相关病毒（AAV）衣壳本身以及针对AAV衍生的转基因的免疫应答。AAV是目前使用最多的病毒载体，因为其相对安全且向非分裂细胞的基因转移效率高。由于DMD是由肌营养不良蛋白基因中的突变或缺失导致的肌营养不良蛋白蛋白的缺乏引起的，因此如动物实验和临床试验所示，使用携带肌营养不良蛋白作为治疗基因的AAV载体的肌营养不良蛋白替代疗法是有效的治疗。由于DMD是一种全身性疾病，因此实现功效所需的AAV载体的量大得不切实际。MSC由于其免疫调节作用而与器官移植组合使用。通过如下所述组合使用MSC和AAV，我们能够降低对AAV衣壳和转基因的免疫应答，以及将AAV的剂量降低至常规临床试验中使用的剂量的约1/100。
Herein, a method to use of mesenchymal stem cells (MSCs) to modulate immune response against rAAV transduction in a canine Duchenne muscular dystrophy (DMD) model is presented. The aim is to overcome the immune response against adeno-associated virus (AAV) capsid itself as well as against the AAV-derived transgene.AAV is currently the most used viral vector because of its relative safety and high efficiency of gene transfer to nondividing cells. Since DMD is caused by a deficiency of dystrophinprotein due to mutation or deletion in the dystrophin gene, dystrophin replacement therapy using AAVvectors carrying dystrophin as a therapeutic gene is an effective treatment as shown by animal experiments and clinical trials. Because DMD is a systemic disease, the amount of AAVvector required to achieve efficacy is impractically large. MSC have been used in combination with organ transplants due to their immunomodulatory effects. By using MSCs and AAVs in combination as described below, we are able to decrease the immune response to AAV capsid and the transgene as well as to reduce the dose of AAV to approximately 1/100 of the dose used in conventional clinical trials.