Charged lipophilic dendrimers: Delivery of oligonucleotides with therapeutic potential

带电亲脂性树枝状聚合物：具有治疗潜力的寡核苷酸的递送

• 批准号: nhmrc : 143090
• 负责人: Prof Elizabeth Rakoczy
• 金额: $ 28.14万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/charged-lipophilic-dendrimers-therapeutic-potential/77688
• 关键词: Charged; lipophilic; dendrimers; Delivery; oligonucleotides

Choroidal neovascularisation, which is the most severe form of Age Related Macular Degeneration (AMD) is the major cause of blindness in the developed world. The disease usually affects people above the age of 75-80. With an ageing population, reaching 3.5 million (over 65) in Australia by year of 2020, AMD is quickly becoming a significant socio-economic problem. Gene therapy could be a cure for the above disease. Currently, there are large numbers of antisense oligonucleotides that have the potential to be developed as new medicines. However, a lack of absorption-cellular uptake and poor in vivo stability are major hurdles that must first be overcome, before any of these compounds will reach the clinic. Synthetic DNA delivery agents are of interest for gene therapy as an alternative to viral vectors, since they carry potentially fewer risks in terms of immuneresponse and propagation. Gene transfer with synthetic compounds is a growing field of research and the largest family of such agents is based on positively charged lipids which are able to self-associate and to form complexes (salts) with DNA conferring a compacted state on the plasmid. Our project will address these major issues through a highly novel strategy involving ion pair formation of lipophilic dendrimer (tree-like compounds with positive charges on the surface) constructs. This multidisciplinary approach has the potential to develop and test new DNA-dendrimer complexes and test them in a well established animal model for neovascularisation. Successful completion of this project might offer a potential therapy for choroidal neovascularisation, with a good chance of entering into human clinical trials by year 2004.

脉络膜新生血管形成是年龄相关性黄斑变性（AMD）的最严重形式，是发达国家失明的主要原因。这种疾病通常影响75-80岁以上的人。随着人口老龄化，到2020年，澳大利亚将达到350万（65岁以上），AMD正在迅速成为一个重大的社会经济问题。基因治疗可能是治疗上述疾病的一种方法。目前，有大量的反义寡核苷酸有潜力被开发为新的药物。然而，缺乏吸收-细胞摄取和体内稳定性差是在这些化合物中的任何一种到达临床之前必须首先克服的主要障碍。合成DNA递送剂作为病毒载体的替代物对于基因治疗是有意义的，因为它们在免疫应答和传播方面具有潜在的更低风险。使用合成化合物的基因转移是一个不断发展的研究领域，并且此类试剂的最大家族是基于带正电荷的脂质，所述脂质能够自缔合并与DNA形成复合物（盐），从而在质粒上赋予压缩状态。我们的项目将通过一种高度新颖的策略来解决这些主要问题，该策略涉及亲脂性树枝状聚合物（表面带正电荷的树状化合物）结构的离子对形成。这种多学科的方法有可能开发和测试新的DNA-树枝状聚合物复合物，并在一个良好的动物模型中测试它们的新血管形成。该项目的成功完成可能为脉络膜新生血管形成提供一种潜在的治疗方法，到2004年有很好的机会进入人体临床试验。