Wagner J A, Messner A H, Moran M L, Daifuku R, Kouyama K, Desch J K, Manley S, Norbash A M, Conrad C K, Friborg S, Reynolds T, Guggino W B, Moss R B, Carter B J, Wine J J, Flotte T R, Gardner P
Department of Molecular Pharmacology, Stanford University School of Medicine, California, USA.
Laryngoscope. 1999 Feb;109(2 Pt 1):266-74. doi: 10.1097/00005537-199902000-00017.
The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients.
A prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted.
Ten patients with previous bilateral maxillary antrostomies were treated.
Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured.
The highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Little or no inflammatory or immune responses were observed.
AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies. A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.
宿主免疫反应和低载体效率一直是囊性纤维化（CF）患者有效进行囊性纤维化跨膜传导调节因子（CFTR）基因转移的关键障碍。在一项I期剂量递增研究中，使用腺相关病毒载体（AAV-CFTR）将CFTR互补DNA（cDNA）导入10例CF患者上颌窦的呼吸道上皮细胞。
进行了一项关于AAV-CFTR的前瞻性、随机、非盲、剂量递增、受试者自身对照的I期临床试验。
10例曾行双侧上颌窦造口术的患者接受了治疗。
测量安全性、通过半定量聚合酶链反应（PCR）检测的基因转移情况以及鼻窦跨上皮电位差（TEPD）。
治疗后2周获取的活检标本中，每细胞AAV-CFTR载体拷贝数在0.1 - 1范围内观察到最高水平的基因转移。检测时，在一名患者中观察到持续41天，在另一名患者中观察到持续10周。治疗后观察到TEPD对药物干预的反应呈剂量依赖性变化。几乎未观察到炎症或免疫反应。
向上颌窦给予AAV-CFTR可成功地将基因剂量依赖性转移至上颌窦，并使鼻窦TEPD发生改变，提示有功能效应，且几乎没有细胞病变或宿主免疫反应。鉴于腺相关病毒载体可能对CFTR基因转移和其他体内基因转移治疗有用，有必要进一步研究。一项关于AAV-CFTR对鼻窦炎临床复发影响的前瞻性、随机、双盲、安慰剂对照、受试者自身对照的II期临床试验将确定AAV基因治疗CF的临床疗效。
