Translational Bypass in Patients with Hemophilia

描述(申请人提供)：我们假设小分子 容易进入细胞可以通过蛋白质合成诱导无意义的抑制 这样的设备，无意义的突变在水平上被翻译为旁路 高达20%。效能评估将与原型一起进行 庆大霉素，一种氨基糖苷类抗生素。如果成功，则为翻译 旁路治疗可能对相当少数的 严重的遗传病。血友病被选为模型病。主修 严重血友病的影响可以消除，只需轻微增加 在要素水平上。血友病是一个有利的系统来确定 庆大霉素基因治疗的直接疗效是因为许多患者 无义突变是可用的，蛋白质产物可以很容易地被测量 积累和腐烂的动力学可以在很短的时间内确定 从蛋白质快速翻转开始的时间。这项拟议的研究有四项 具体目标： 1.在最初的10组试验中评估庆大霉素对无义突变的抑制作用 重度血友病患者B。 2.确定庆大霉素诱导的废话之间是否存在相关性 抑制和基因(因子VIII或因子IX)、终止密码子类型和序列 背景。 3.确定庆大霉素是否抑制了5例移码突变 血友病A或B患者和5名患者中的错义突变 血友病A或B。 4.确定庆大霉素的作用是否能与常规药物保持一致 使用庆大霉素的时间长达12周。 胡说八道的抑制者可能会彻底改变血友病的治疗方法 缺乏现成要素替代的欠发达国家 带有血液传播病原体的风险。有效的废话抑制器 应该对30,000-40,000人中的任何一个人的无义突变有效 基因。废话抑制剂在治疗癌症方面也可能是有益的。 这是由于肿瘤抑制基因的无义突变造成的。

DESCRIPTION (provided by applicant): We hypothesize that small molecules that readily enter cells can induce nonsense suppression by the protein synthetic apparatus such, that nonsense mutations are translationally bypassed at levels up to 20 percent. Evaluation of efficacy will be performed with the prototype drug gentamicin, an aminoglycoside antibiotic. If successful, translational bypass therapy could be beneficial for a significant minority of patients with severe genetic disease. Hemophilia is chosen as the model disease. Major effects of severe hemophilia A)B can be eliminated with only a slight increase in factor level. The hemophilias are an advantageous system to determine directly the efficacy of gentamicin gene therapy because many patients with nonsense mutations are available, the protein product can be measured readily and the kinetics of accumulation and decay can be determined over a short period since the proteins turn over rapidly. The proposed study has four specific aims: 1.Assess gentamicin suppression of nonsense mutations in an initial set of ten patients with severe hemophilia B. 2.Determine if there is a correlation between gentamicin-induced nonsense suppression and gene (factor VIII or IX), stop codon type, and sequence context. 3.Determine whether gentainicin suppresses frameshift mutations in five patients with hemophilia A or B and missense mutations in five patients with hemophilia A or B. 4.Determine whether the effect of gentamicin can be maintained with regular administration of gentamicin for up to twelve weeks. Nonsense suppressors could revolutionize therapy for hemophilia in underdeveloped countries where factor replacement is not readily available and carries risks of blood-borne pathogens. An efficacious nonsense suppressor should be effective in nonsense mutations in any of the 30,000 -40,000 human genes. Nonsense suppressors also may be beneficial in the treatment of cancers that result from nonsense mutation in tumor suppressor genes.