Crystalline Antiproliferative Drugs for Intraocular Diseases

描述(申请人提供)：几种重要的视网膜疾病是由眼内细胞过度增殖引起的；我们计划通过一种新的药理学方法来针对主要的疾病，包括创伤引起的视网膜脱离和增殖性玻璃体视网膜病变，以及老年性黄斑变性中的脉络膜新生血管。使用局部治疗视网膜疾病的主要问题之一是大多数眼内药物的半衰期很短，必须经常给药。有一个重要的未得到满足的需求是开发一种方法来延长玻璃体内或类似剂量的抗增殖药物的眼内持续时间。我们开发了一种新的化学方法来修饰核苷，这种方法具有低溶解度和长效的抗增殖或抗病毒活性。在一次玻璃体内注射后，我们已经证明了原型化合物的持续生物活性长达20周或更长时间。我们的首要目标是开发长效晶状药物，这种药物可以小体积地注射到眼睛的玻璃体腔中。由于这些晶体化合物的化学设计具有低水溶性，它们将作为极长效的抗增殖化合物发挥作用，有助于减少上述疾病和其他视网膜疾病造成的视网膜损伤和视力损失。这笔赠款主要用于增殖性疾病，但我们强调，如果这种晶体药物输送系统在动物和未来的人类研究中取得成功，它将能够扩展到治疗许多其他眼内疾病。这笔赠款是两个研究小组的合作，雅各布斯视网膜中心的视网膜研究实验室(Freeman博士和程博士)和部门的Karl Hostetler博士。医学专业，两人都在加州大学圣迭戈分校。Hostetler博士的团队以合成和评估脂质核苷类似物而闻名，而Freeman博士的团队在眼内药物和视网膜疾病动物模型的开发和表征方面非常熟练。我们将共同合成和评估晶体最低限度可溶抗增殖化合物的关键脂质类似物。不同的体外和体内评估将确定最佳的结构和配方变量，以提供高治疗指数和长眼内半衰期。最好的化合物和配方将在上述重要视网膜疾病的公认动物模型中进行测试。该项目可能提供作用时间长、安全、治疗指数高的药物，并可能为重要的视网膜疾病带来新的药物和治疗方法。 公共卫生相关性：这项研究拨款将允许开发一种长效眼内注射，该注射将防止视网膜脱离，并减少因年龄相关性黄斑变性而形成的疤痕造成的损害。我们的研究小组已经发现了修改小的抗增殖分子的方法，使它们在眼睛中持续5个月以上，因此是帮助预防这些严重失明原因的最佳选择。

DESCRIPTION (provided by applicant): Several important retinal disease are caused by excess proliferation of cells in the eye; major ones which we plan to target with a novel pharmacologic approach include retinal detachment due to trauma and proliferative vitreoretinopathy as well as choroidal neovascularization in age related macular degeneration. One of the major problems in using local therapy for retinal diseases is the short half-life of most intraocular drugs that must be administered frequently. There is an important unmet need to develop a way to prolong the intraocular duration of intravitreally or similarly administered antiproliferative drugs. We have developed a novel chemical method of modifying nucleosides which provides for low solubility and long-acting antiproliferative or antiviral activity. Following a single intravitreal injection, we have already demonstrated persistent biological activity of prototype compounds for up to 20 weeks or longer. Our overarching goal is to develop long acting crystalline drugs that can be injected into the vitreous cavity in the eye in small volumes. Because these crystalline compounds are chemically designed to have low water solubility, they will act as extremely long acting anti-proliferative compounds which will help reduce retinal damage and vision loss from the above diseases and other retinal diseases. This grant focuses on diseases of proliferation but we stress that should this crystalline drug delivery system be successful in animal and in the future, in human studies, it will be able to be extended for treatment of many other intraocular diseases. This grant is a collaboration of two research groups, the Retina Research Laboratory at the Jacobs Retina Center (Drs. Freeman and Cheng) and Dr. Karl Hostetler in the Dept. of Medicine, both at UCSD. Dr. Hostetler's group is well known for synthesis and evaluation of lipid nucleoside analogs while Dr. Freeman's group is highly skilled in development and characterization of intraocular drugs and animal models of retinal disease. Together, we will synthesize and evaluate key lipid analogs of crystalline minimally soluble anti-proliferative compounds. Various in vitro and in vivo evaluations will determine the optimal structural and formulation variables to provide for a high therapeutic index and long intraocular half life. The best compounds and formulations will be tested in accepted animal models of the important retinal diseases mentioned above. This project may provide drugs with a prolonged duration of action which will be safe and have a high therapeutic index and may lead to new agents and treatment methods for important retinal diseases. Public Health Relevance: This research grant will allow the development of a long-acting intraocular injection that will prevent retina detachment and reduce the damage due to scarring from age-related macular degeneration. Our research group has discovered ways to modify small antiproliferative molecules so that they last for over 5 months in the eye and are thus optimal to help prevent these severe causes of blindness.