Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
Neurosci Lett. 2012 Oct 11;527(2):90-9. doi: 10.1016/j.neulet.2012.04.078. Epub 2012 May 17.
Our Translational Gene Therapy Center has used small molecules for exon skipping and mutation suppression and gene transfer to replace or provide surrogate genes as tools for molecular-based approaches for the treatment of muscular dystrophies. Exon skipping is targeted at the pre-mRNA level allowing one or more exons to be omitted to restore the reading frame. In Duchenne Muscular Dystrophy (DMD), clinical trials have been performed with two different oligomers, a 2'O-methyl-ribo-oligonucleoside-phosphorothioate (2'OMe) and a phosphorodiamidate morpholino (PMO). Both have demonstrated early evidence of efficacy. A second molecular approach involves suppression of stop codons to promote readthrough of the DMD gene. We have been able to establish proof of principle for mutation suppression using the aminoglycoside, gentamicin. A safer, orally administered, alternative agent referred to as Ataluren (PTC124) has been used in clinical trials and is currently under consideration for approval by the FDA. Using a gene therapy approach, we have completed two trials and have initiated a third. For DMD, we used a mini-dystrophin transferred in adeno-associated virus (AAV). In this trial an immune response was seen directed against transgene product, a quite unexpected outcome that will help guide further studies. For limb girdle muscular dystrophy 2D (alpha-sarcoglycan deficiency), the transgene was again transferred using AAV but in this study, a muscle specific creatine kinase promoter controlled gene expression that persisted for six months. A third gene therapy trial has been initiated with transfer of the follistatin gene in AAV directly to the quadriceps muscle. Two diseases with selective quadriceps muscle weakness are undergoing gene transfer including sporadic inclusion body myositis (sIBM) and Becker muscular dystrophy (BMD). Increasing the size and strength of the muscle is the goal of this study. Most importantly, no adverse events have been encountered in any of these clinical trials.
我们的转化基因治疗中心已经使用小分子进行外显子跳跃、突变抑制和基因转移，以替代或提供替代基因，作为治疗肌肉萎缩症的基于分子的方法的工具。外显子跳跃针对的是前体 mRNA 水平，允许一个或多个外显子被省略以恢复阅读框架。在杜氏肌营养不良症（DMD）中，已经用两种不同的寡聚物进行了临床试验，一种是 2'O-甲基-核糖寡核苷酸-硫代磷酸酯（2'OMe）和一种磷酰胺酸吗啉寡聚物（PMO）。两者都显示出早期疗效的证据。第二种分子方法涉及抑制终止密码子以促进 DMD 基因的通读。我们已经能够使用氨基糖苷类抗生素庆大霉素建立突变抑制的原理证明。一种更安全、可口服的替代药物称为 Ataluren（PTC124）已在临床试验中使用，目前正在考虑由 FDA 批准。使用基因治疗方法，我们已经完成了两项试验，并启动了第三项。对于 DMD，我们使用 mini-dystrophin 转移到腺相关病毒（AAV）中。在这项试验中，观察到针对转基因产物的免疫反应，这是一个相当意外的结果，将有助于指导进一步的研究。对于肢带型肌肉萎缩症 2D（alpha-肌聚糖缺乏症），转基因再次通过 AAV 转移，但在这项研究中，肌肉特异性肌酸激酶启动子控制基因表达持续了六个月。第三项基因治疗试验已经启动，使用 AAV 将 follistatin 基因直接转移到股四头肌。两种选择性股四头肌无力的疾病正在进行基因转移，包括散发性包涵体肌炎（sIBM）和 Becker 肌营养不良症（BMD）。增加肌肉的大小和力量是这项研究的目标。最重要的是，在这些临床试验中没有遇到任何不良事件。
