Translational Bypass in Patients with Hemophilia

描述（由申请人提供）：我们假设， 容易进入细胞可以诱导无义抑制的蛋白质合成 这样的装置，无义突变在水平上被谨慎地绕过， 高达20%。将使用原型进行疗效评价 庆大霉素，一种氨基糖苷类抗生素。如果成功，翻译 旁路治疗可能对极少数患者有益， 严重的遗传病。选择血友病作为模型疾病。主要 重度血友病A）B的影响只需轻微增加即可消除 因素水平。血友病是一个有利的系统来确定 直接影响庆大霉素基因治疗的疗效，因为许多患者 无义突变是可用的，蛋白质产物可以容易地测量 积累和衰减的动力学可以在短时间内确定， 这是因为蛋白质迅速转变。研究报告提出了四个 具体目标： 1.评估庆大霉素对初始10个无义突变的抑制 重度血友病B患者。 2.确定庆大霉素诱导的无意义之间是否存在相关性 抑制和基因（因子VIII或IX）、终止密码子类型和序列 上下文 3.确定gentainicin是否抑制五种基因的移码突变 A型或B型血友病患者，5例 血友病A或B。 4.确定庆大霉素的效果是否可以维持与定期 庆大霉素给药长达12周。 无意义抑制剂可以彻底改变血友病的治疗方法， 不发达国家，这些国家的要素替代不容易获得， 会带来血液传播病原体的风险。一种有效的无意义抑制剂 在30，000 - 40，000人中的任何一个人的无义突变中都应该有效， 基因.无义抑制因子也可能对癌症的治疗有益 肿瘤抑制基因无义突变。

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.