Department of Biotechnology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali 160062, Punjab, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali 160062, Punjab, India.
Int J Biol Macromol. 2024 Oct;277(Pt 2):134097. doi: 10.1016/j.ijbiomac.2024.134097. Epub 2024 Jul 25.
A considerable fraction of population in the world suffers from rare diseases. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and its related Cas proteins offer a modern form of curative gene therapy for treating the rare diseases. Hereditary transthyretin amyloidosis, hereditary angioedema, duchenne muscular dystrophy and Rett syndrome are a few examples of such rare diseases. CRISPR/Cas9, for example, has been used in the treatment of β-thalassemia and sickle cell disease (Frangoul et al., 2021; Pavani et al., 2021) [1,2]. Neurological diseases such as Huntington's have also been focused in some studies involving CRISPR/Cas (Yang et al., 2017; Yan et al., 2023) [3,4]. Delivery of these biologicals via vector and non vector mediated methods depends on the type of target cells, characteristics of expression, time duration of expression, size of foreign genetic material etc. For instance, retroviruses find their applicability in case of ex vivo delivery in somatic cells due to their ability to integrate in the host genome. These have been successfully used in gene therapy involving X-SCID patients although, incidence of inappropriate activation has been reported. On the other hand, ex vivo gene therapy for β-thalassemia involved use of BB305 lentiviral vector for high level expression of CRISPR biological in HSCs. The efficacy and safety of these biologicals will decide their future application as efficient genome editing tools as they go forward in further stages of human clinical trials. This review focuses on CRISPR/Cas based therapies which are at various stages of clinical trials for treatment of rare diseases and the constraints and ethical issues associated with them.
世界上相当一部分人口患有罕见病。成簇规律间隔短回文重复序列（CRISPR）及其相关的 Cas 蛋白为治疗罕见病提供了一种现代形式的治愈性基因疗法。遗传性转甲状腺素淀粉样变性、遗传性血管性水肿、杜氏肌营养不良症和雷特综合征就是此类罕见病的几个例子。例如，CRISPR/Cas9 已被用于治疗 β-地中海贫血和镰状细胞病（Frangoul 等人，2021 年；Pavani 等人，2021 年）[1,2]。一些涉及 CRISPR/Cas 的研究也集中在神经退行性疾病上，如亨廷顿病（Yang 等人，2017 年；Yan 等人，2023 年）[3,4]。通过载体和非载体介导方法递送这些生物制剂取决于靶细胞类型、表达特性、表达持续时间、外源遗传物质大小等。例如，逆转录病毒由于能够整合到宿主基因组中，因此在体外递送体细胞时具有适用性。尽管已经报道了不适当激活的情况，但它们已成功用于涉及 X-SCID 患者的基因治疗。另一方面，β-地中海贫血的体外基因治疗涉及使用 BB305 慢病毒载体在 HSCs 中高水平表达 CRISPR 生物。这些生物制剂的疗效和安全性将决定它们作为高效基因组编辑工具的未来应用，因为它们将在人类临床试验的进一步阶段取得进展。本综述重点介绍了处于罕见病治疗临床试验不同阶段的基于 CRISPR/Cas 的疗法，以及与之相关的限制和伦理问题。
