Development of an antisense oligonucleotide therapy for SOD1 Familial ALS

描述（由申请人提供）：SOD1突变导致约2%的肌萎缩性侧索硬化症（ALS），这是一种成人发病的神经退行性疾病，以运动神经元丧失为特征，导致严重无力、肌肉萎缩和死亡，通常在3-5年内继发于呼吸衰竭。动物模型和人体研究表明，降低SOD1水平具有保护作用。我们已经开发出反义寡核苷酸，当传递到脑脊液时，可以降低脑和脊髓中的SOD1。其中一种反义寡核苷酸已在一期人体临床试验中进行了测试，并在低剂量下证明了极好的安全性。然而，从随后的研究中可以清楚地看出，我们需要为人类SOD1开发新的反义寡核苷酸。Timothy Miller， Merit Cudkowicz和Isis制药公司在本次资助中概述的合作工作将通过在啮齿动物和非人灵长类动物中进行毒理学研究以及在SOD1G93A大鼠研究中测试功效来确定更有效，更安全的SOD1反义寡核苷酸。这些研究的成功完成将导致SOD1相关ALS的新SOD1反义寡核苷酸的IND。

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.