Gene therapy matures to medicines.
Gene therapy matures to medicines.
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基因疗法成熟为药物。
DOI：
10.1093/hmg/ddz182
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发表时间：
2019
影响因子：
3.5
通讯作者：
Arruda,ValderR
中科院分区：
文献类型：
--
作者：
Davidson,BeverlyL;Arruda,ValderR
三年前，《人类分子遗传学》委托编写了一份关于基因治疗方法和进展的纲要(1)。当时，我们已经见证了该领域的大幅增长和发展，并且正在进行人体试验，与2011年的阶段相比，这是一个坚实的进步(2)。2016年，我们接近于批准基因试剂，这些试剂一旦交付，将对人们的生活产生巨大而积极的影响。今天，有些药物得到了联邦药物管理局和欧洲药物管理局的批准。监管机构已经批准了遗传性疾病的治疗方法，包括罕见的遗传性视网膜营养不良（由基因RPE65的常染色体隐性突变引起），运动神经元疾病（1型脊髓性肌萎缩症，SMA-1）和脂蛋白脂肪酶缺乏症，尽管后者已不再可用。此外，慢病毒介导的原发性免疫缺陷和遗传性血红蛋白病的体外矫正已被批准。对于获得性疾病，修饰表达嵌合抗原受体的T细胞（CAR-T细胞）获得了B细胞恶性肿瘤的监管批准，为类似CAR-T类型治疗的发展奠定了基础。虽然每一种药物都需要付出巨大的努力才能获得批准，但现在已经为其他药物铺平了道路。在这一期中，我们汇集了来自各个领域的专家的评论，这些领域的基因治疗方法正在发展和完善。这些综述概述了我们迄今为止的进展，解释了具体适应症仍存在的障碍，并讨论了未来进展的路线图。在过去的几十年里，基因治疗领域的许多人进行了细致而周到的科学研究，他们的辛勤工作终于结出了果实——无论是年轻人还是老年人，患有遗传性遗传病或获得性疾病（如癌症）的患者都经历了深刻的改善。最近在病毒和非病毒载体方面取得了重要进展，以及持续进步的技术，这些技术可能为新的翻译应用打开大门。对于慢病毒载体，转基因表达盒利用宿主细胞调节因子来加强基因表达的控制。而且，通过在载体生产过程中扩大用于病毒粒子假型的包膜的种类，细胞靶向的范围和效率正在得到提高。对于重组腺相关病毒等被封装的载体，体内进化、衣壳重组和新血清型的不断发现加深了病毒粒子的工具箱，可以为特定组织或细胞类型提供更低剂量或更高特异性的转导。提高正在表达的基因产物的活性是另一个重要的进步，因为它降低了产生效力所需的载体剂量。事实上，用于血友病B （FIX缺乏症）的因子IX (FIX) Padua的活性比野生型蛋白增加了8倍。同样，一种抗镰状血红蛋白变体正被用于治疗镰状细胞病和地中海贫血患者。因此，基因治疗的进展不仅通过基因传递技术的改进，而且通过使用基因编辑技术和蛋白质工程的进步而得到扩展。例如，通过开发具有更高特异性活性的分子来降低载体的剂量，或者通过开发截断的蛋白质来保留功能并适应基因传递载体的包装限制（例如B结构域缺失的FVIII；微营养不良蛋白和替代的CRISPR系统）。这些发现应该鼓励研究人员找出具有可利用特征的变异。
Three years ago, Human Molecular Genetics commissioned a compendium on gene therapy approaches and advances (1). At that time, we had already witnessed substantial growth and development in the field and were in the midst of human trials, a solid advance from the stage that existed in 2011 (2). In 2016 we were closing in on possible approvals for genetic reagents that, when delivered, would dramatically and positively affect people’s lives. Today, there are drugs approved by both the Federal Drug Administration and European Medicines Agency. Regulatory agencies have approved treatments for inherited disorders including a rare inherited retinal dystrophy (caused by autosomal recessive mutations in the gene RPE65), a motor neuron disease (spinal muscular atrophy type 1, SMA-1) and a lipoprotein lipase deficiency, although the latter is no longer available for use. In addition, lentiviral-mediated ex vivo correction of primary immunodeficiencies and inherited hemoglobinopathies have been approved. For acquired disorders, T cells modified to express chimeric antigen receptors (CAR-T cells) received regulatory approval for B cell malignancies, setting the stage for similar CAR-T type therapy development. While individually each drug required enormous effort for approval, the path has now been paved for others to follow. In this issue, we have compiled reviews from experts in various fields where gene therapy approaches are being developed and refined. These reviews outline where we are to date, explain the barriers that remain for specific indications and discuss the roadmap for future advances. The hard work of careful and thoughtful scientific studies by many in the gene therapy field over the past several decades is finally bearing fruit—measured in the profound improvements experienced by patients, young and aged, with inherited genetic diseases or acquired disorders such as cancer. There has been recent important progress in viral and non-viral vectors, as well as the technologies for continued advancements that could open the door for new translational applications. For lentivirus vectors transgene expression cassettes are taking advantage of host-cell regulatory factors for enhanced control of gene expression. And, the scope and efficiency of cell targeting are being improved by expanding the variety of envelopes used to pseudotype the virion during vector production. For encapsidated vectors like recombinant adenoassociated viruses, in vivo evolution, capsid shuffling and the continued discovery of new serotypes deepen the toolbox of virions that can provide for transduction at lower doses or greater specificity for a given tissue or cell type. Improving the activity of the gene product being expressed is another important step forward, as it lowers the vector doses required for efficacy. Indeed, factor IX (FIX) Padua for hemophilia B (FIX deficiency) has 8-fold increased activity compared to the wild-type protein. Similarly, an anti-sickling hemoglobin variant is being used for the treatment of patients with sickle cell disease and thalassemia. Thus gene therapy advances are being extended not only by improvements in gene delivery technology but also through the use of advances in gene editing technologies and protein engineering. For example, through development of higher specific activity molecules that allow lower doses of vector, or of truncated proteins that preserve function and fit the packaging limitations of gene delivery vehicles (eg B domain-deleted FVIII; microdystrophins and alternative CRISPR systems). These discoveries should encourage researchers to identify variants with characteristics that can be harnessed …