CRISPR-Cas9-based treatment of myocilin-associated glaucoma
CRISPR-Cas9-based treatment of myocilin-associated glaucoma
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DOI：
10.1073/pnas.1706193114
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发表时间：
2017-10-17
影响因子：
11.1
通讯作者：
Sheffield, Val C.
中科院分区：
文献类型：
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作者：
Jain, Ankur;Zode, Gulab;Sheffield, Val C.
原发性开角型青光眼（POAG）是全球范围内不可逆视力丧失的主要原因，眼内压（IOP）升高是主要危险因素。据报道，肌球蛋白（MYOC）显性功能获得性突变发生在4%的POAG病例中。MYOC突变导致蛋白质错误折叠，导致小梁网（TM）（调节IOP的组织）中的内质网（ER）应激。我们在培养的人TM细胞和POAG的MYOC小鼠模型中使用CRISPR-Cas9介导的基因组编辑来敲低突变MYOC的表达，从而缓解ER应激。体内基因组编辑导致较低的IOP并防止进一步的青光眼损伤。重要的是，使用离体人体器官培养系统，我们证明了人类基因组编辑在这种重要疾病中的可行性。
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin (MYOC) dominant gain-of-function mutations have been reported in similar to 4% of POAG cases. MYOC mutations result in protein misfolding, leading to endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that regulates IOP. We use CRISPR-Cas9-mediated genome editing in cultured human TM cells and in a MYOC mouse model of POAG to knock down expression of mutant MYOC, resulting in relief of ER stress. In vivo genome editing results in lower IOP and prevents further glaucomatous damage. Importantly, using an ex vivo human organ culture system, we demonstrate the feasibility of human genome editing in the eye for this important disease.