Project 1: Therapeutic Gene Editing for Spinal Muscular Atrophy (Trailblazer)

项目1（SMA） 脊髓性肌萎缩症（SMA）是一种进行性运动神经元疾病（MND），是导致脊髓性肌萎缩症的主要遗传原因。 所有族裔群体的婴儿死亡率。SMA是由基本生存运动的纯合性丧失引起的 神经元1（SMN 1）基因，而一个或多个拷贝的高度相似的SMN 2基因部分补偿 SMA患者SMN 1丢失，与SMN 2相反，SMN 1在6位C·G至T·A的变化为 外显子7（C6 T）。这种变化导致mRNA剪接过程中外显子7的跳跃，并产生截短的SMNΔ7 蛋白质在细胞中迅速降解。这种快速降解导致SMN蛋白不足，运动功能丧失， 神经元麻痹和死亡最常见的SMA类型I型患者， SMN蛋白水平，如果不治疗，中位年龄为6个月。 在这个开拓者项目中，我们的目标是（1）优化Δ7 SMA小鼠的碱基编辑治疗方案;（2）评估 SMA小鼠中的生物分布、脱靶和毒性特征;以及（3）进行大规模功效研究。我们 将与基因编辑核心密切合作，为IND生成基因编辑结果的严格分析 提交我们的开拓者项目，我们将与临床前小鼠模型核心密切协调， 分析来自大规模疗效研究的样本。这一开拓性项目的成功成果也将 告知用于在所有后续项目中开发基于基因组编辑的治疗线索的策略。

PROJECT SUMMARY PROJECT 1 (SMA) Spinal Muscular Atrophy (SMA) is a progressive motor neuron disease (MND) and the leading genetic cause of infant mortality across all ethnic groups. SMA is caused by the homozygous loss of the essential survival motor neuron 1 (SMN1) gene and while one or more copies of the highly similar SMN2 gene partially compensates for the loss of SMN1 in SMA patients, SMN1, in contrast to SMN2, contains a C·G-to-T·A change at position 6 of exon 7 (C6T). This change leads to skipping of exon 7 during mRNA splicing and the resulting truncated SMNΔ7 protein is rapidly degraded in cells. This rapid degradation results in SMN protein insufficiency, loss of motor neurons, paralysis, and death. Patients with the most common form of SMA, type I, have a ~10-fold reduction in SMN protein levels and live to a median age of 6 months if untreated. In this trailblazer project, we aim to (1) Optimize base editing treatment protocols in Δ7 SMA mice; (2) Assess biodistribution, off-targets, and toxicity profiles in SMA mice; and (3) Conduct large-scale efficacy studies. We will work closely with the Gene Editing core to generate rigorous analyses of gene editing outcomes for the IND submission of our trailblazer project, and we will coordinate closely with the Preclinical Mouse Model Core to analyze samples from large-scale efficacy studies. The successful outcomes of this trailblazer project will also inform the strategies used to develop genome editing-based therapeutic leads in all Follower Projects.