Advances in CRISPR therapeutics.
Advances in CRISPR therapeutics.
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DOI：
10.1038/s41581-022-00636-2
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发表时间：
2023-01
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--
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rna引导的原核CRISPR相关（Cas）蛋白可以在哺乳动物基因组中产生靶向双链断裂，这一发现催化了聚集规律间隔短回文重复（CRISPR）的复兴。这一发现导致了CRISPR系统的发展，该系统利用天然DNA修复机制比以往任何时候都更容易、更精确地修复缺陷基因。在临床前研究和一些临床试验中，CRISPR已被用于敲除有害的突变基因，修复编码序列中的错误，以挽救疾病表型。然而，大多数遗传疾病是由基因组编码区和非编码区突变、缺失和重复的组合引起的，因此需要复杂的基因组工程策略，而不仅仅是简单的基因敲除。为了克服这一限制，自然和工程CRISPR-Cas系统的工具箱已经大大扩展到包括在人类细胞中进行精确基因组编辑和表观基因组工程的各种工具。CRISPR技术应用于编辑非编码基因组、调节基因调控、进行精确的遗传改变和靶向传染病，有可能为许多以前无法治疗的疾病带来治愈性治疗。本综述的重点是CRISPR在治疗无法通过诱导编码基因的帧移或过早停止来克服的疾病方面的潜在应用。作者讨论了Cas9之外的Cas蛋白工程和CRISPR系统，这些系统创建了一个工具箱来设计人类基因组。CRISPR系统是rna引导的核糖核蛋白，既可以作为序列特异性核酸靶向蛋白，也可以作为核酸酶；这些系统被开发用来治疗简单的孟德尔障碍。使用新发现的CRISPR系统和Cas蛋白工程的新方法扩大了可用的基因组工程工具箱，使具有复杂驱动因素的疾病的潜在治愈疗法的发展成为可能。用CRISPR靶向和改变非编码基因组可能通过改变靶基因的转录或翻译来潜在地改善疾病。使用CRISPR系统将核酸酶死亡的Cas蛋白融合到转录或表观遗传调节剂中，可以在不诱导DNA损伤或改变遗传密码的情况下进行靶向基因调控。CRISPR碱基编辑器和引物编辑器可用于创建精确的基因组编辑，例如使用野生型CRISPR - cas核酸酶难以实现的治疗性突变、插入或删除。除了基因组工程，CRISPR工具箱还可能用于预防和治疗传染病。
The clustered regularly interspaced short palindromic repeats (CRISPR) renaissance was catalysed by the discovery that RNA-guided prokaryotic CRISPR-associated (Cas) proteins can create targeted double-strand breaks in mammalian genomes. This finding led to the development of CRISPR systems that harness natural DNA repair mechanisms to repair deficient genes more easily and precisely than ever before. CRISPR has been used to knock out harmful mutant genes and to fix errors in coding sequences to rescue disease phenotypes in preclinical studies and in several clinical trials. However, most genetic disorders result from combinations of mutations, deletions and duplications in the coding and non-coding regions of the genome and therefore require sophisticated genome engineering strategies beyond simple gene knockout. To overcome this limitation, the toolbox of natural and engineered CRISPR–Cas systems has been dramatically expanded to include diverse tools that function in human cells for precise genome editing and epigenome engineering. The application of CRISPR technology to edit the non-coding genome, modulate gene regulation, make precise genetic changes and target infectious diseases has the potential to lead to curative therapies for many previously untreatable diseases. This Review focuses on the potential applications of CRISPR to treat diseases that cannot be overcome by inducing frameshifts or premature stops in coding genes. The authors discuss Cas protein engineering and CRISPR systems beyond Cas9 that create a toolbox to engineer the human genome. CRISPR systems are RNA-guided ribonucleoproteins that function as both sequence-specific nucleic acid-targeting proteins and nucleases; these systems are being developed as therapies for simple Mendelian disorders. Novel approaches using newly discovered CRISPR systems and Cas protein engineering have expanded the available genome engineering toolbox, enabling the development of potentially curative therapies for diseases with complex drivers. Targeting and altering the non-coding genome with CRISPR could potentially ameliorate disease by changing the transcription or translation of target genes. The use of CRISPR systems with nuclease-dead Cas proteins fused to transcriptional or epigenetic modulators enables targeted gene regulation without inducing DNA damage or altering the genetic code. CRISPR base editors and prime editors can be used to create precise genome edits such as therapeutic mutations, insertions or deletions that are difficult to achieve using wild-type CRISPR–Cas nucleases. In addition to genome engineering, the CRISPR toolbox could potentially be used to prevent and treat infectious diseases.
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