Advancing RNA Therapeutics for Huntington’s Disease

摘要 亨廷顿病的原因是三核苷酸CAG重复序列从 36次重复到36次或更多重复。重复次数的模式为42次，大多数 患者的年龄在40到45岁之间。这种疾病一般在30岁到40岁之间开始发病， 伴随着认知受损、抑郁和异常运动的发生和发展。这个 遗传学是常染色体显性遗传。在HD动物模型中降低突变的亨廷顿蛋白延迟 疾病的发作或减轻疾病的严重性。我们使用先进的，改进型的，双- 分支siRNA，通过在大脑中调用RNA干扰来降低突变的亨廷顿蛋白。我们的 先进的siRNA实现了治疗优势：以非 人类灵长类动物单次给药后长期狩猎素的降低 脑脊液。为安全起见，将对siRNA进行结构优化和初步 结果将会得到保护。这项创建建议的目标是为有希望的 治疗亨廷顿病的治疗学。类似的治疗方法可能适用于 其他常染色体显性遗传性神经疾病。

ABSTRACT The cause of Huntington’s disease is an increase in the trinucleotide CAG repeat from under 36 repeats to 36 or greater repeats. The mode for the number of repeats is 42, and most patients have between 40 and 45. The disease generally starts between ages 30 and 40, with onset and progression of impaired cognition, depression, and aberrant movement. The genetics is autosomal dominant. Lowering mutant huntingtin in HD animal models delays onset of disease or mitigates the severity of disease. We use advanced, modified, di- branched siRNA to lower mutant huntingtin, by invoking RNA interference in brain. Our advanced siRNA achieves therapeutic advantages: spread throughout the brain in non- human primate and long-term huntingtin lowering after a single administration into the cerebrospinal fluid. The siRNA will be optimized in structure for safety and preliminary results will be secured. The goal of this CREATE proposal is to set the stage for promising therapeutics for treatment of Huntington’s disease. Similar treatments could be applicable to other autosomal dominant neurological disorders.