Development of new injectable, PolyGeneCaP composites for gene therapy

开发用于基因治疗的新型可注射 PolyGeneCaP 复合材料

• 批准号: EP/F019599/1
• 负责人: Margaret Lawrence
• 金额: $ 3.21万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF019599%2F1
• 关键词: Development; new; injectable; PolyGeneCaP; composites

The aim of gene therapy is to treat patients who are born with inherited diseases by providing a normal gene to repair or replace the damaged or missing gene. Potential applications of gene therapy include well-known diseases such as haemophilia, cystic fibrosis, muscular dystrophy, some types of cancer and many other disorders where the defective genes are now being identified. Current procedures for the introduction of healthy genes into the cells of affected patients have relied primarily on the use of virus-derived 'carriers', but there is growing concern that these agents are not yet well enough understood and have the potential to be dangerous, even fatal. Unfortunately, alternative synthetic gene-delivery systems have thus far been inefficient and have had only very limited success. In this project we are proposing to develop a non-viral delivery system that has a specific healthy gene entrapped within a safe chemical particle. We plan to use a new method to convert these into very small 'nanoparticles' (called GeneCaP) that fully surround the gene and therefore protect it from breakdown and also enable it to get more readily into the patient's cells. To increase further the efficiency of gene entry, which has been one of the major problems in gene therapy, we will place the GeneCaP into a novel liquid (PolyGeneCaP) which can be injected. This will be designed so that it will rapidly solidify very close to the diseased organ and then degrade slowly, releasing the encased GeneCaP adjacent to the cell where the gene is needed to function. The 'model' disease which will be used in this proposal is called Sly Disease (Mucopolysaccharidosis Type VII), one of a large group of lysosomal gene defects which result in progressive mental and physical disability and are usually fatal at an early age. Illness occurs because the defective gene is unable to produce a particular lysosomal protein, which when restored in the presence of the healthy gene alleviates the disease. In this study we will, for the first time, measure and carefully correlate the properties of the DNA-containing particles and the ability of these new 'gene-drugs' to help correct the MPS VII disease, in order to be able to develop the optimal treatment strategies for a range of genetic diseases.

基因疗法的目的是通过提供正常基因来修复或替代受损或缺失的基因来治疗患有遗传疾病的患者。基因疗法的潜在应用包括众所周知的疾病，例如血友病，囊性纤维化，肌肉营养不良，某些类型的癌症以及许多其他疾病，现在正在鉴定出缺陷的基因。当前将健康基因引入受影响患者细胞的程序主要依赖于病毒衍生的“载体”，但是人们越来越担心这些药物还不够充分理解，并且有可能危险，甚至致命。不幸的是，迄今为止，替代合成基因分散系统的效率低下，成功的成功效率非常有限。在这个项目中，我们提议开发一种非病毒递送系统，该系统具有特定的健康基因，夹在安全的化学粒子中。我们计划使用一种新方法将它们完全围绕该基因的小“纳米颗粒”（称为genecap）转换为很小的“纳米颗粒”（称为GeneCap），因此可以保护其免受分解，并使其能够更容易进入患者的细胞。为了进一步提高基因进入的效率，这是基因治疗的主要问题之一，我们将将基因置于可以注射的新型液体（PolygeneCap）中。这将被设计为使其迅速凝固非常接近患病器官，然后缓慢降解，从而释放出相邻基因功能的细胞附近的包含的Genecap。该提案中将使用的“模型”疾病称为狡猾的疾病（粘多糖型VII型），这是一大批溶酶体基因缺陷之一，导致渐进的精神和身体残疾，通常在很小的时候是致命的。发生疾病是因为缺陷的基因无法产生特定的溶酶体蛋白，在存在健康基因的情况下恢复后，该蛋白会减轻该疾病。在这项研究中，我们将首次测量并仔细地将含DNA颗粒的特性以及这些新的“基因毒品”的能力帮助纠正MPS VII疾病，以便能够为一系列遗传疾病制定最佳治疗策略。