Translational Bypass in Patients with Hemophilia

血友病患者的转化搭桥

• 批准号: 6464855
• 负责人: STEVE Seev SOMMER
• 金额: $ 35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6464855
• 关键词: blood disorder chemotherapy; clinical research; coagulation factor IX; coagulation factor VIII; drug screening /evaluation; frameshift mutation; gene induction /repression; gene therapy; genetic terminator element; genetic translation; gentamicins; hemophilia As; hemophilia B; human subject; human therapy evaluation; patient oriented research; point mutation

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.

描述（由申请人提供）：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义抑制 这样的装置，无义突变在水平上被翻译绕过 高达 20%。将使用原型进行功效评估 药物庆大霉素，一种氨基糖苷类抗生素。如果成功的话，翻译 搭桥疗法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。主要的 只需轻微增加即可消除严重血友病 A)B 的影响 在因素水平上。血友病是确定的有利系统 直接影响庆大霉素基因治疗的疗效，因为许多患者 无义突变可用，蛋白质产物可以轻松测量 积累和衰变的动力学可以在短时间内确定 蛋白质快速更新的时期。拟议的研究有四个 具体目标： 1.评估庆大霉素对初始十个突变组中无义突变的抑制作用 严重血友病患者 B. 2.确定庆大霉素引起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 语境。 3.确定庆大霉素是否抑制五种基因的移码突变 患有 A 型或 B 型血友病的患者以及 5 名患有错义突变的患者 血友病 A 或 B。 4.确定定期用药能否维持庆大霉素的效果 庆大霉素的给药时间长达十二周。 无意义的抑制剂可能会彻底改变血友病的治疗 要素替代不方便的不发达国家 携带血源性病原体的风险。有效的废话抑制器 应该对 30,000 -40,000 名人类中任何一个的无义突变有效 基因。无义抑制器也可能有益于癌症的治疗 这是由肿瘤抑制基因的无义突变引起的。