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High-Efficiency, Selection-free Gene Repair in Airway Stem Cells from Cystic Fibrosis Patients Rescues CFTR Function in Differentiated Epithelia.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2019-12-11 , DOI: 10.1016/j.stem.2019.11.002
Sriram Vaidyanathan 1 , Ameen A Salahudeen 2 , Zachary M Sellers 1 , Dawn T Bravo 3 , Shannon S Choi 2 , Arpit Batish 2 , Wei Le 3 , Ron Baik 1 , Sean de la O 2 , Milan P Kaushik 1 , Noah Galper 1 , Ciaran M Lee 4 , Christopher A Teran 3 , Jessica H Yoo 2 , Gang Bao 4 , Eugene H Chang 5 , Zara M Patel 3 , Peter H Hwang 3 , Jeffrey J Wine 6 , Carlos E Milla 1 , Tushar J Desai 2 , Jayakar V Nayak 3 , Calvin J Kuo 2 , Matthew H Porteus 1
Affiliation  

Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mortality in CF patients is mostly due to respiratory sequelae. Challenges with gene delivery have limited attempts to treat CF using in vivo gene therapy, and low correction levels have hindered ex vivo gene therapy efforts. We have used Cas9 and adeno-associated virus 6 to correct the ΔF508 mutation in readily accessible upper-airway basal stem cells (UABCs) obtained from CF patients. On average, we achieved 30%-50% allelic correction in UABCs and bronchial epithelial cells (HBECs) from 10 CF patients and observed 20%-50% CFTR function relative to non-CF controls in differentiated epithelia. Furthermore, we successfully embedded the corrected UABCs on an FDA-approved porcine small intestinal submucosal membrane (pSIS), and they retained differentiation capacity. This study supports further development of genetically corrected autologous airway stem cell transplant as a treatment for CF.

中文翻译:


囊性纤维化患者气道干细胞中的高效、无选择基因修复可挽救分化上皮细胞中的 CFTR 功能。



囊性纤维化 (CF) 是一种由囊性纤维化跨膜电导调节因子 (CFTR) 基因突变引起的单基因疾病。 CF患者的死亡主要是由于呼吸道后遗症。基因递送的挑战限制了使用体内基因疗法治疗 CF 的尝试,并且较低的校正水平阻碍了离体基因疗法的努力。我们使用 Cas9 和腺相关病毒 6 来纠正从 CF 患者获得的易于获取的上呼吸道基底干细胞 (UABC) 中的 ΔF508 突变。平均而言,我们在 10 名 CF 患者的 UABC 和支气管上皮细胞 (HBEC) 中实现了 30%-50% 的等位基因校正,并在分化的上皮细胞中观察到相对于非 CF 对照的 20%-50% CFTR 功能。此外,我们成功地将校正后的 UABC 嵌入 FDA 批准的猪小肠粘膜下膜 (pSIS) 上,并且它们保留了分化能力。这项研究支持进一步开发基因校正的自体气道干细胞移植作为 CF 的治疗方法。
更新日期:2019-12-13
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