Development of a novel, potent, safe, long-lasting lentivirus-based gene therapy for cystic fibrosis

开发一种新型、有效、安全、持久的基于慢病毒的囊性纤维化基因疗法

• 批准号: MR/J014699/1
• 负责人: Deborah Gill
• 金额: $ 163.2万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ014699%2F1
• 关键词: Development; novel; potent; safe; long

Cystic Fibrosis (CF) is a common genetic disease that affects over 8000 people in the UK. It is the result of a mutation in a single gene called CFTR that causes the build up of thick sticky mucus in the lungs. Eventually the lungs become repeatedly infected and inflamed, leading to lung failure and premature death. All current therapies are aimed at coping with the symptoms; there is no cure. In 2001, three research groups in the UK formed the CF Gene Therapy Consortium to develop a new kind of treatment based on introducing new (healthy) copies of the CFTR gene into the lungs of people with CF. Many advances have been made, and we have learned a great deal about the obstacles to this approach, but we are not yet in a position to offer an effective gene therapy for CF lung disease. The aim of this research application is to use a new kind of gene therapy based on a virus called lentivirus, which we think has the potential to be more efficient at delivering the gene into the lungs and to provide an effective treatment for CF lung disease. In order to make the lentivirus carrying the CF gene as effective as possible, it is wrapped up in two new coat proteins called F and HN, a process known as 'pseudotyping'. We have shown that when the lentivirus is pseudotyped with F and HN it is efficient at entering lung cells and the gene it carries can be expressed for many months, even years in some situations. Another key feature that this pseudotyped virus displays is that it can be repeatedly administered, a property we have not seen previously with other viruses. This has an important advantage for treating chronic diseases, such as CF where the effects last for the life-time of the individual. The objectives of this application are i) to engineer the virus so it is suitable for use in patients; ii) to improve virus production methods so that it can be made in sufficient quantities to use as a therapy; and iii) to understand the potential for side-effects associated with administering the virus. The research project is 18 months long and at the end of it we hope to have selected a final version of the virus that we can take forward to test in patients. If we are successful in manufacturing the virus and selecting a suitable version to give to patients, we envisage that it could be delivered to the lungs of CF individuals using a device called a nebuliser, which generates a fine mist that can be breathed in. The increased efficiency of this virus along with the ability to have an effect that is long-lived effect means that this could form the basis of a new, more effective treatment for CF.

囊性纤维化 (CF) 是一种常见的遗传病，在英国影响着 8000 多人。这是 CFTR 单一基因突变的结果，导致肺部积聚浓稠的粘液。最终肺部反复感染和发炎，导致肺衰竭和过早死亡。目前所有的疗法都是为了应对症状；没有治愈方法。 2001 年，英国的三个研究小组成立了 CF 基因治疗联盟，旨在开发一种新的治疗方法，将 CFTR 基因的新（健康）副本引入 CF 患者的肺部。已经取得了许多进展，我们也了解到很多关于这种方法的障碍，但我们还无法为 CF 肺病提供有效的基因治疗。这项研究应用的目的是使用一种基于慢病毒的新型基因疗法，我们认为这种疗法有可能更有效地将基因传递到肺部，并为 CF 肺部疾病提供有效的治疗。为了使携带 CF 基因的慢病毒尽可能有效，它被包裹在两种名为 F 和 HN 的新外壳蛋白中，这一过程称为“假型化”。我们已经证明，当慢病毒用F和HN假型化时，它可以有效地进入肺细胞，并且它携带的基因可以表达数月，在某些情况下甚至数年。这种假型病毒表现出的另一个关键特征是它可以重复施用，这是我们以前在其他病毒中未见过的特性。这对于治疗慢性疾病（例如CF）具有重要的优势，其效果将持续到个体的一生。该应用的目标是 i) 改造病毒，使其适合患者使用； ii) 改进病毒生产方法，以便能够生产足够数量的病毒用于治疗； iii) 了解与施用病毒相关的潜在副作用。该研究项目为期 18 个月，我们希望在项目结束时选择出病毒的最终版本，以便在患者身上进行测试。如果我们成功地制造出这种病毒并选择合适的版本提供给患者，我们设想可以使用一种称为雾化器的装置将其输送到 CF 个体的肺部，该装置会产生可以吸入的细雾。这种病毒效率的提高以及产生长期效果的能力意味着这可能成为一种新的、更有效的 CF 治疗方法的基础。

项目成果

LARGE-SCALE PRODUCTION OF LENTIVIRAL VECTORS FOR CF LUNG GENE THERAPY

用于 CF 肺基因治疗的慢病毒载体的大规模生产

• 发表时间: 2014
• 作者: Davies, LA

704. Enhanced Lentiviral Production Through Rational Design of Mammalian Host Cells

704. 通过哺乳动物宿主细胞的合理设计增强慢病毒生产

• DOI: 10.1016/s1525-0016(16)33512-2
• 发表时间: 2016
• 期刊: Molecular Therapy
• 影响因子: 12.4
• 作者: Gelinas J

534. Preparation for a First-in-Man Lentivirus Trial in Cystic Fibrosis Patients

534. 囊性纤维化患者首次慢病毒试验的准备

• DOI: 10.1016/s1525-0016(16)33343-3
• 发表时间: 2016
• 期刊: Molecular Therapy
• 影响因子: 12.4
• 作者: Griesenbach U

Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis.

• DOI: 10.1136/thoraxjnl-2016-208406
• 发表时间: 2017-02
• 期刊: Thorax
• 影响因子: 10
• 作者: Alton EW;Beekman JM;Boyd AC;Brand J;Carlon MS;Connolly MM;Chan M;Conlon S;Davidson HE;Davies JC;Davies LA;Dekkers JF;Doherty A;Gea-Sorli S;Gill DR;Griesenbach U;Hasegawa M;Higgins TE;Hironaka T;Hyndman L;McLachlan G;Inoue M;Hyde SC;Innes JA;Maher TM;Moran C;Meng C;Paul-Smith MC;Pringle IA;Pytel KM;Rodriguez-Martinez A;Schmidt AC;Stevenson BJ;Sumner-Jones SG;Toshner R;Tsugumine S;Wasowicz MW;Zhu J
• 通讯作者: Zhu J

Pediatric Pulmonary

小儿肺科

• 发表时间: 2014
• 作者: Davidson H