Xu Jie, Livraghi-Butrico Alessandra, Hou Xia, Rajagopalan Carthic, Zhang Jifeng, Song Jun, Jiang Hong, Wei Hong-Guang, Wang Hui, Bouhamdan Mohamad, Ruan Jinxue, Yang Dongshan, Qiu Yining, Xie Youming, Barrett Ronald, McClellan Sharon, Mou Hongmei, Wu Qingtian, Chen Xuequn, Rogers Troy D, Wilkinson Kristen J, Gilmore Rodney C, Esther Charles R, Zaman Khalequz, Liang Xiubin, Sobolic Michael, Hazlett Linda, Zhang Kezhong, Frizzell Raymond A, Gentzsch Martina, O'Neal Wanda K, Grubb Barbara R, Chen Y Eugene, Boucher Richard C, Sun Fei
Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan (UM) Medical Center, Ann Arbor, Michigan, USA.
Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
JCI Insight. 2021 Jan 11;6(1):139813. doi: 10.1172/jci.insight.139813.
Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of approximately 40 days and died of gastrointestinal disease, but therapeutic regimens directed toward restoring gastrointestinal transit extended median survival to approximately 80 days. Surrogate markers of exocrine pancreas disorders were found in CF rabbits with declining health. CFTR expression patterns in WT rabbit airways mimicked humans, with widespread distribution in nasal respiratory and olfactory epithelia, as well as proximal and distal lower airways. CF rabbits exhibited human CF-like abnormalities in the bioelectric properties of the nasal and tracheal epithelia. No spontaneous respiratory disease was detected in young CF rabbits. However, abnormal phenotypes were observed in surviving 1-year-old CF rabbits as compared with WT littermates, and these were especially evident in the nasal respiratory and olfactory epithelium. The CF rabbit model may serve as a useful tool for understanding gut and lung CF pathogenesis and for the practical development of CF therapeutics.
现有的囊性纤维化（CF）动物模型为CF发病机制提供了关键见解，但受限于寿命短、缺乏关键表型和/或维护成本高。在此，我们报告了通过CRISPR/Cas9介导产生的CF兔模型，该模型具有相对较长的寿命且维护和护理成本较低。仅补充口服渗透性泻药的CF兔中位生存期约为40天，死于胃肠道疾病，但针对恢复胃肠运输的治疗方案将中位生存期延长至约80天。在健康状况下降的CF兔中发现了外分泌胰腺疾病的替代标志物。野生型兔气道中的CFTR表达模式与人类相似，在鼻呼吸和嗅觉上皮以及近端和远端下呼吸道广泛分布。CF兔在鼻和气管上皮的生物电特性方面表现出类似人类CF的异常。在幼年CF兔中未检测到自发性呼吸道疾病。然而，与野生型同窝仔兔相比，在存活的1岁CF兔中观察到异常表型，这些在鼻呼吸和嗅觉上皮中尤为明显。CF兔模型可能是理解肠道和肺部CF发病机制以及CF治疗方法实际开发的有用工具。
