Development of an antisense oligonucleotide therapy for SOD1 Familial ALS

描述(申请人提供)：SOD1突变导致约2%的肌萎缩侧索硬化症(ALS)，这是一种成人起病的神经退行性疾病，其特征是运动神经元丧失，导致严重虚弱、肌肉萎缩，通常在3-5年内继发于呼吸肌衰竭。动物模型和人体研究表明，降低SOD1水平将具有保护作用。我们已经开发出反义寡核苷酸，当被输送到脑脊液中时，可以降低大脑和脊髓中的SOD1。其中一种反义寡核苷酸在I期人体临床试验中被测试，并在测试的低剂量下显示出极好的安全性。然而，从后续的研究中可以清楚地看出，我们需要开发新的针对人SOD1的反义寡核苷酸。蒂莫西·米勒、Merit Cudkowicz和Isis PharmPharmticals在这笔赠款中概述的合作工作将通过在啮齿动物和非人类灵长类动物身上进行毒理学研究，并通过在SOD1G93A大鼠研究中测试疗效，定义一种更有效、更安全的SOD1反义寡核苷酸。这些研究的成功完成将导致新的SOD1反义寡核苷酸的IND用于SOD1相关的ALS。

DESCRIPTION (provided by applicant): Mutations in SOD1 cause approximately 2% of amyotrophic lateral sclerosis (ALS), an adult onset neurodegenerative disease characterized by loss of motor neurons resulting in severe weakness, muscle atrophy, and death typically in 3-5 years secondary to failure of respiratory muscles. Animal models and human studies suggest that lowering levels of SOD1 would be protective. We have developed antisense oligonucleotides that lower SOD1 in the brain and spinal cord when delivered to the cerebral spinal fluid. One of these antisense oligonucleotides was tested in a Phase I human clinical trial and demonstrated excellent safety at the low doses tested. However, it is clear from subsequent studies that we need to develop new antisense oligonucleotides for human SOD1. The collaborative work between Timothy Miller, Merit Cudkowicz and Isis Pharmaceuticals outlined in this grant will define a more potent, safer SOD1 antisense oligonucleotide by performing toxicology studies in rodents and non-human primates and by testing efficacy in the SOD1G93A rat studies. The successful completion of these studies will lead to an IND for the new SOD1 antisense oligonucleotide for SOD1-related ALS.