Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia, USA.
Curr Opin Neurol. 2011 Oct;24(5):415-22. doi: 10.1097/WCO.0b013e32834aa3f1.
As the first genetic disease for which the culpable gene was identified by positional cloning, Duchenne muscular dystrophy has served as a paradigm for therapeutic approaches to neuromuscular disease, in which role it has proved especially testing. The large mass and broad distribution of the target tissue, skeletal muscle, have stretched the patience and ingenuity of those seeking therapeutic delivery of the largest known gene. The most promising recent advances are summarized in this article.
The main obstacle to genetic therapies has been the development of vectors able to efficiently deliver large, potentially therapeutic, genetic constructs to the large and widely dispersed mass of body musculature. Recombinant viral vectors that efficiently transduce muscle are unable to carry the full-length construct. Myogenic cells that are able both to carry full-length genes and to repair muscles are technically challenging to produce in sufficient quantity. A recent promising approach is the use of agents that obviate the mutation.
Although genetic and cell-mediated approaches are currently showing genuine promise in preclinical and clinical trials, there remains considerable interest in the development of agents that ameliorate the downstream pathology. One general challenge is the three-way tension between the interests of patients, regulators, and the biotechnology industry.
目的综述：作为第一个通过定位克隆确定致病基因的遗传性疾病，杜氏肌营养不良症为神经肌肉疾病的治疗方法提供了范例，在这方面，它被证明是一个特别具有挑战性的范例。目标组织——骨骼肌的巨大质量和广泛分布，考验了那些寻求将已知最大基因进行治疗性递送的人的耐心和创造力。本文总结了最近的一些最有前途的进展。
最新发现：基因治疗的主要障碍是开发能够将大型潜在治疗性基因构建体高效递送至广泛分布的大量身体肌肉组织的载体。能够高效转导肌肉的重组病毒载体无法携带全长构建体。能够携带全长基因并修复肌肉的肌源性细胞在技术上难以大量生产。最近一个有前途的方法是使用可以避免突变的药物。
总结：尽管基因和细胞介导的方法在临床前和临床试验中目前确实显示出了真正的前景，但人们仍然对开发改善下游病理的药物有很大的兴趣。一个普遍的挑战是患者、监管机构和生物技术行业三方利益之间的三方面紧张关系。
