PDF(Pubmed)
Abstract：
Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.
摘要：
由于罕见疾病的数量和总体患病率，它们共同对社会造成了很高的影响。他们的异质性，多样性,和自然给管理和治疗带来了严峻的临床挑战。在这次审查中,我们讨论了罕见疾病基因治疗临床应用的最新进展，专注于各种病毒和非病毒策略。在Luxturna的背景下讨论了腺相关病毒（AAV）载体的使用，已被批准用于治疗视网膜上皮中的RPE65缺乏症。Immygic,一种被许可用于治疗难治性转移性黑色素瘤的疱疹病毒载体，将是针对罕见癌症开发的溶瘤载体的一个例子。Yescarta和Kymriah将展示逆转录病毒和慢病毒载体在自体离体生产嵌合抗原受体T细胞（CAR-T）中的应用，获得治疗难治性白血病和淋巴瘤的许可。类似的逆转录病毒和慢病毒技术可以应用于自体造血干细胞，例如Strimvelis和Zynteglo，分别获得腺苷脱氨酶-重度联合免疫缺陷（ADA-SCID）和β-地中海贫血的许可治疗。反义寡核苷酸技术将通过Onpattro和Tegsedi得到强调，用于家族性甲状腺素运载蛋白（TTR）淀粉样变性的RNA干扰药物，和Spinraza,脊髓性肌萎缩症（SMA）的剪接转换治疗。使用Zolgensma可以初步比较AAV和寡核苷酸疗法在SMA中的有效性，AAV血清型9载体，还有Spinraza.通过这些上市的基因疗法和基因细胞疗法的例子，我们将讨论这种新技术在以前难以解决的罕见疾病中的扩展应用。
