A gene therapy for cystic fibrosis using GP64-pseudotyped lentivirus

摘要/项目总结 这个提议的I/II期（快速通道）SBIR项目将产生一个基因， 一种治疗囊性纤维化（CF）的方法，在单次吸入给药后， 无论他们有什么样的致病突变。CF是一种危及生命的疾病， CFTR基因中数百种有记录的常染色体隐性突变之一。CFTR紊乱 干扰气道和肠道中的粘液纤毛运输和抗菌活性， 以及对最终致命的呼吸道感染的易感性。目前的治疗包括对症气道 支持物（例如，粘液溶解剂）或CFTR调节剂，它们中没有一种解决疾病进展，并且其中许多 仅对CF致病突变的一个子集有效。到目前为止，没有治愈CF和平均寿命 CF患者的预期寿命为39岁。 基因治疗有可能成为CF领域的游戏规则改变者，提供一种通用的治疗方法。 然而，对于被认为是CF的临床相关选择的基因治疗，实质性疗效仍然是未知的。 需要-主要的限制因素是运载工具有效和高效地投放大载荷的能力 比如CFTR Talee Bio在爱荷华州大学和儿童医院的学术创始人和合作者 在这一领域有超过25年的经验。最近，我们开发了一种专有的 慢病毒基因治疗技术可以解决CF的这种需求，具有携带大有效载荷的能力 并用一种包膜蛋白进行基因工程改造， 上皮细胞我们的初步数据表明，我们的产品原型可以有效地提供CFTR， 在体外和体内的气道上皮细胞中，这种表达持续至少两年，并且它没有显示出 遗传毒性的证据。在这里，我们将验证我们的临床就绪产品（第1阶段）的有效性，并将 开展初始生物分布和安全性工作，以便与FDA召开IND前会议。 Talee Bio得到了拥有100多年集体经验的学术合作者的支持 CF生物学、病理学和基因治疗，并由一个在药物治疗方面具有丰富经验的管理团队管理。 发展Talee已经从一个基金会（艾米丽的随行人员）和一个投资者那里筹集了资金， 风险投资，以加快这一SBIR的成果进入临床。

ABSTRACT/PROJECT SUMMARY The product that will result from this proposed Phase I/II (Fast-Track) SBIR project will be a gene therapy for cystic fibrosis (CF) that will, following a single inhalational administration, be curative to all people with CF regardless of the specific causative mutation they have. CF is a life-threatening disease caused by any one of the hundreds of documented autosomal recessive mutations in the CFTR gene. Derangement of CFTR interferes with mucociliary transport and antibacterial activity in the airways and gut and a buildup of mucous and susceptibility to airway infections that is ultimately lethal. Current treatments include symptomatic airway support (e.g., mucolytics) or CFTR modulators, none of which address disease progression and many of which have efficacy for only a subset of CF-causative mutations. To date there is no cure for CF and the average life expectancy of a person with CF is 39 years. Gene therapy has the potential to be a game-changer in the field of CF, by offering a universal cure. However, for gene therapy to be considered to be a clinically relevant option for CF, substantial efficacy is still needed – the main limiting factor is the ability of a vector to effectively and efficiently deliver a large payload like CFTR. Talee Bio's academic founders and collaborators at the University of Iowa and Children's Hospital of Philadelphia have more than 25 years of experience in this field. Recently, we developed a proprietary lentivirus gene therapy technology that could address this need for CF, with the ability to carry a large payload and genetically engineered with an envelope protein which increases binding and entry to the surface of airway epithelial cells. Our preliminary data indicate that a prototype of our product can deliver CFTR effectively to airway epithelial cells in vitro and in vivo, that expression persists for at least two years, and that it shows no evidence of genotoxicity. Here we will validate the efficacy of our clinic-ready product (phase 1), and will conduct the initial biodistribution and safety work that will enable a pre-IND meeting with the FDA. Talee Bio is supported by academic collaborators with more than 100 years of collective experience in CF biology, pathology, and gene therapy, and by a management team with demonstrable experience in drug development. Talee has raised financing from a foundation (Emily's Entourage) and from an investor, Phase 1 Ventures, to accelerate the outcomes of this SBIR into the clinic.