Advancing RNA Therapeutics for Huntington’s Disease

摘要 亨廷顿舞蹈病的病因是三核苷酸CAG重复序列从 36个重复至36个或更多个重复。重复次数的众数是42， 患者的年龄在40到45岁之间。这种疾病通常在30到40岁之间开始， 伴随认知受损、抑郁和异常运动的发作和进展。的 遗传学是常染色体显性遗传。降低HD动物模型中的突变亨廷顿蛋白延迟 疾病的发作或减轻疾病的严重程度。我们使用先进的、修改的、di- 分支的siRNA通过在大脑中引发RNA干扰来降低突变的亨廷顿蛋白。我们 先进的siRNA实现了治疗优势：在非脑内扩散， 人类灵长类动物和长期亨廷顿蛋白降低后，单次给药到 脑脊液为了安全和初步的目的，siRNA将在结构上进行优化。 结果将得到保证。这一CREATE提案的目标是为有前途的 用于治疗亨廷顿病的治疗剂。类似的治疗方法也适用于 其他常染色体显性遗传神经系统疾病。

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.