New CRISPR Tools to Correct Pathogenic Mutations in Usher Syndrome.
New CRISPR Tools to Correct Pathogenic Mutations in Usher Syndrome.
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DOI：
10.3390/ijms231911669
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发表时间：
2022-10-01
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传性视网膜变性是英国导致失明的主要原因。近年来，在解决这一问题方面取得了重大进展，FDA批准的一种开创性的基因疗法(Luxturna®)针对的是RPE65基因功能突变的丧失。然而，这种形式的基因替代疗法仍然存在明显的缺点。特别是，超过4.7kb的腺相关病毒(AAV)包装限制的基因序列缺乏生存能力，或者功能突变的毒性获得。例如，~15.7kb的USH2A基因对于AAV来说太大了：它是一种安全有效的载体，能够转导光感受器细胞进行基因替代治疗。Usher综合征是一种临床和遗传异质性的常染色体隐性遗传的聋盲综合征。USH2A基因编码USH2 A蛋白，定位于光感受器纤毛细胞和耳蜗毛细胞。USH2A基因突变导致Usher综合征II型(USH2)，这是Usher综合征最常见的亚型，也是本综述的重点。到目前为止，研究人员还无法创造出一种高效、安全的编辑工具，这种工具小到足以容纳在单个AAV载体中，以便输送到人类细胞中。本文回顾了源自细菌防御机制的CRISPR技术克服这些挑战的潜力；提供工具来精确编辑和纠正USH2A中的小插入、缺失和碱基转换，而不需要提供全长基因。这种超紧凑型疗法可以在与年轻人失明的一个重要原因作斗争方面取得进展。
Inherited retinal degenerations are a leading cause of blindness in the UK. Significant advances have been made to tackle this issue in recent years, with a pioneering FDA approved gene therapy treatment (Luxturna®), which targets a loss of function mutation in the RPE65 gene. However, there remain notable shortcomings to this form of gene replacement therapy. In particular, the lack of viability for gene sequences exceeding the 4.7 kb adeno-associated virus (AAV) packaging limit or for toxic gain of function mutations. The USH2A gene at ~15.7 kb for instance is too large for AAV delivery: a safe and effective vehicle capable of transducing photoreceptor cells for gene replacement therapy. Usher Syndrome is a clinically and genetically heterogenous deaf-blindness syndrome with autosomal recessive inheritance. The USH2A gene encodes the protein usherin, which localises to the photoreceptor cilium and cochlear hair cells. Mutations in the USH2A gene cause Usher Syndrome type II (USH2), which is the most common subtype of Usher Syndrome and the focus of this review. To date, researchers have been unable to create an efficient, safe editing tool that is small enough to fit inside a single AAV vector for delivery into human cells. This article reviews the potential of CRISPR technology, derived from bacterial defence mechanisms, to overcome these challenges; delivering tools to precisely edit and correct small insertions, deletions and base transitions in USH2A without the need to deliver the full-length gene. Such an ultra-compact therapy could make strides in combating a significant cause of blindness in young people.
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