Charged lipophilic dendrimers: Delivery of oligonucleotides with therapeutic potential

脉络膜新生血管是最严重的老年性黄斑变性(AMD)，是发达国家致盲的主要原因。这种疾病通常影响75-80岁以上的人。随着澳大利亚人口老龄化，到2020年，澳大利亚的AMD人口将达到350万(65岁以上)，AMD正迅速成为一个重大的社会经济问题。基因疗法可能是治愈上述疾病的一种方法。目前，有大量的反义寡核苷酸具有作为新药开发的潜力。然而，缺乏吸收--细胞摄取和体内稳定性差是这些化合物进入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方案，在基因治疗方面引起了人们的兴趣，因为它们在免疫应答和繁殖方面潜在的风险更小。用合成化合物进行基因转移是一个不断发展的研究领域，这类药物中最大的一类是基于带正电荷的脂类，这些脂类能够自结合并与DNA形成络合物(盐)，从而使质粒处于紧凑的状态。我们的项目将通过一种非常新颖的策略来解决这些主要问题，该策略涉及到亲脂树状大分子(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-树状大分子复合体，并在建立良好的新生血管动物模型中测试它们。该项目的成功完成可能为脉络膜新生血管提供一种潜在的治疗方法，很有可能在2004年进入人类临床试验。

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.