Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107;
Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11199-11204. doi: 10.1073/pnas.1706193114. Epub 2017 Oct 2.
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin () dominant gain-of-function mutations have been reported in ∼4% of POAG cases. 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.
原发性开角型青光眼 (POAG) 是全球范围内导致不可逆视力丧失的主要原因，眼内压 (IOP) 升高是主要的危险因素。已在约 4%的 POAG 病例中报道了肌球蛋白 () 显性获得性功能突变。这些突变导致蛋白质错误折叠，导致调节 IOP 的小梁网 (TM) 内质网 (ER) 应激。我们使用 CRISPR-Cas9 介导的基因编辑在培养的人 TM 细胞和 POAG 的 MYOC 小鼠模型中敲低突变 MYOC 的表达，从而缓解 ER 应激。体内基因编辑可降低 IOP 并防止进一步的青光眼损伤。重要的是，我们使用体外人器官培养系统证明了对这种重要疾病进行人基因组编辑的可行性。
