Aerosol delivery of HDAd into Primate Lungs: Preclinical CF Gene Therapy Studies

HDAd 气雾剂递送至灵长类动物肺部：临床前 CF 基因治疗研究

• 批准号: 7391537
• 负责人: Philip Ng
• 金额: $ 70.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391537
• 关键词: Acute; Address; Aerosols; Affect; Age; Alternative Therapies; Bronchoscopes; Caucasians; Caucasoid Race; Chloride Channels; Chronic; Clinical; Code; Condition; Cystic Fibrosis; Data; Disease; Distal; Dose; Epithelial Cells; Epithelium; Frequencies; Gene Transduction Agent; Gene Transfer; Generations; Gland; Goals; Immune response; Incidence; Individual; Infection; Inflammation; Live Birth; Lobar; Lobe; Lung; Lung diseases; Mediating; Membrane; Methods; Morbidity - disease rate; Mucous body substance; Mus; Mutation; Organ; Papio; Pneumonia; Primates; Publishing; Regulator Genes; Research; Respiratory Failure; Safety; Serotyping; Single-Gene Defect; Testing; Tidal Volume; Toxic effect; Trachea; Transduction Gene; Viral; Visual; aerosolized; airway epithelium; base; cystic fibrosis patients; desire; gene therapy; gene transfer vector; helper-dependent adenoviral vector; lung lobe; mortality; nonhuman primate; novel; pre-clinical; response; transduction efficiency; transgene expression; vector

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common fatal autosomal recessive disease among Caucasians, with a frequency of ~1 in 2500 live births and is caused by recessive mutations in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene which encodes a membrane chloride channel present in the epithelium of the lung and other organs. Morbidity and mortality in CF patients is due to lung disease characterized by inflammation, obstructive mucus and persistent infection. CF is currently inadequately treatable and CF patients inevitably succumb to respiratory failure at a median age of -32 years. Clearly novel therapies are needed and the desire to develop gene therapy to treat CF is high. However, despite over a decade of research, CF gene therapy has remained elusive. Chief among the obstacles to successful gene therapy are 1) inefficient gene transfer to the airway epithelium and submucosal glands, 2) toxicity of the gene transfer vectors and 3) the challenge of vector readministration. Therefore, the objective of this proposal is to specifically address each of these limitations. This will be accomplished by evaluating the safety and efficacy of a novel method of delivering helper-dependent adenoviral vectors (HDAd) into the lungs of nonhuman primates. HDAd are deleted of all viral coding sequences and are superior to first generation, E1-deleted, Ad vectors in terms of reduced toxicity and longer duration of transgene expression. We have recently developed novel methods to deliver HDAd into the lungs of nonhuman primates and have obtained exceedingly high and unprecedented levels of transduction of the airway epithelium and submucosal glands with negligible toxicity and minimal pulmonary inflammation. Therefore, we propose to build upon these encouraging preliminary results in this proposal. Specific Aim 1 is to optimize and assess the safety and efficacy of intratracheal aerosolization of HDAd to achieve uniform transduction throughout the lung. Specific Aim 2 is to optimize and assess the safety and efficacy of targeted lobar aerosolization of HDAd to achieve uniform transduction throughout the lung. Specific Aim 3 is to investigate the duration of transgene expression following pulmonary transduction and chronic toxicity. Specific Aim 4 is to investigate the safety and efficacy of various strategies of pulmonary readministration of HDAd. Successful completion of these Specific Aims will provide an important first step towards clinical CF gene therapy.

描述（由申请人提供）：囊性纤维化（CF）是高加索人中最常见的致命常染色体隐性疾病，频率约为2500个活生生，是由囊性纤维化跨膜传播率调节性（CFTR）基因中的隐性突变引起的，该基因培养了Esmbrane Channe and epithel and epithel and epithel的含量。 CF患者的发病率和死亡率是由于肺部疾病的特征是炎症，阻塞性粘液和持续感染。 CF目前的治疗不足，CF患者不可避免地屈服于中位年龄-32岁的呼吸衰竭。显然需要新颖的疗法，并且需要开发基因疗法治疗CF的愿望很高。但是，尽管研究了十多年，但CF基因疗法仍然难以捉摸。成功基因疗法的障碍中的主要是1）效率低下的基因转移到气道上皮和粘膜下腺，2）基因转移载体的毒性和3）矢量恢复的挑战。因此，该提案的目的是专门解决这些局限性。这将通过评估将辅助腺病毒载体（HDAD）传递到非人类灵长类动物的肺部的新型方法的安全性和功效来实现。 HDAD均被所有病毒编码序列删除，并且优于第一代，E1删除，AD载体在降低毒性和更长的转基因表达持续时间方面。我们最近开发了新的方法，可以将HDAD输送到非人类灵长类动物的肺中，并获得了气道上皮和粘膜下腺的过度和前所未有的水平，具有可忽略的毒性和最小的肺部炎症。因此，我们建议在这一提案中以这些令人鼓舞的初步结果为基础。具体目的1是优化和评估HDAD气管内气化的安全性和功效，以在整个肺部实现均匀的转导。具体目标2是优化和评估HDAD靶向LOBAR雾化以在整个肺部实现均匀转导的安全性和功效。具体目的3是研究肺转导和慢性毒性后转基因表达的持续时间。特定目的4是研究HDAD肺部再也管理策略的安全性和功效。这些特定目标的成功完成将为临床CF基因治疗提供重要的第一步。