Bravo Dawn T, Vaidyanathan Sriram, Baker Jeannette, Sinha Vrishti, Tsai Esmond, Roozdar Pooya, Kong William W, Atkinson Patrick J, Patel Zara M, Hwang Peter H, Rao Vidya K, Negrin Robert S, Wine Jeffrey J, Milla Carlos, Sellers Zachary M, Desai Tushar J, Porteus Matthew H, Nayak Jayakar V
Division of Rhinology, Department of Otolaryngology, Stanford University School of Medicine, Stanford CA.
Center for Gene Therapy, Institute at Nationwide Children's Hospital, Columbus, OH.
bioRxiv. 2025 Jan 26:2025.01.24.634776. doi: 10.1101/2025.01.24.634776.
Modulator agents that restore cystic fibrosis transmembrane conductance regulator (CFTR) function have revolutionized outcomes in cystic fibrosis, an incurable multisystem disease. Barriers exist to modulator use, making local CFTR gene and cell therapies attractive, especially in the respiratory tract. We used CRISPR to gene-correct CFTR in upper airway basal stem cells (UABCs) and show durable local engraftment into recipient murine respiratory epithelium. Interestingly, the human cells recapitulate the organization and differentiation of human sinus epithelium, with little expansion or contraction of the engrafted population over time, while retaining expression of the CFTR transgene. Our results indicate that human airway stem cell transplantation with locoregional restoration of CFTR function is a feasible approach for treating CF and potentially other diseases of the respiratory tract.
能够恢复囊性纤维化跨膜传导调节因子（CFTR）功能的调节剂已经彻底改变了囊性纤维化（一种无法治愈的多系统疾病）的治疗效果。调节剂的使用存在障碍，这使得局部CFTR基因和细胞疗法颇具吸引力，尤其是在呼吸道疾病治疗方面。我们使用CRISPR对鼻道基底干细胞（UABCs）中的CFTR进行基因校正，并显示其能持久地局部植入受体小鼠呼吸道上皮。有趣的是，人类细胞重现了人类鼻窦上皮的组织和分化过程，随着时间推移，植入群体几乎没有扩张或收缩，同时保留了CFTR转基因的表达。我们的结果表明，通过局部恢复CFTR功能进行人类气道干细胞移植是治疗囊性纤维化以及潜在的其他呼吸道疾病的一种可行方法。
