Nusinersen

Nusinersen is an SMN-ASO that increases SMN levels by blocking an intronic splice silencer in SMN2, thereby facilitating the exon 7 inclusion and generation of FL-SMN2 transcripts^[1].

Nusinersen(6.5mg/kg; I.C.V.) robustly rescues the growth curve of SMN∆7 mice, enhances motor function and dramatically reduces αMN loss and prevents the disruption and loss of canonical Cajal bodies (CBs) in αMNs of the SMA mouse. Also, Nusinersen treatment normalizes the distribution of the protein synthesis machinery and polyadenylated mRNAs in SMNΔ7 mice^[2]. Nusinersen was administered to rabbits as an intrathecally (IT) bolus dose of 1.8 mg/kg to the first group, intravenously (IV) bolus dose of 1 mg/kg to the second group, respectively. The C_max, AUC_last and C₀ of IV were 15.6±4.88μg/mL, 17.8±4.10 h*μg/mL and 17.6±6.20μg/mL; the T_max, C_max and AUC_last of IT were 1h, 6.0±0.10μg/mL and 12.4±1.15 h*μg/mL, respectively. The calculated bioavailability of nusinersen was 33 %^[3].

References:
[1] Torres-Benito L, Schneider S, Rombo R, et al. NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorates spinal muscular atrophy in mice[J]. The American Journal of Human Genetics, 2019, 105(1): 221-230.
[2] Berciano M T, Puente-Bedia A, Medina-Samamé A, et al. Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly (A) RNA distribution in a SMA mouse model[J]. Scientific reports, 2020, 10(1): 10738.
[3] Zhang X, Sha C, Zhang W, et al. Development and validation of an HILIC/MS/MS method for determination of nusinersen in rabbit plasma[J]. Heliyon, 2024, 10(10).

Nusinersen是一种脊髓性肌萎缩症反义寡核苷酸（SMN-ASO），它通过阻断 SMN2 基因内含子中的一个剪接沉默子来提高运动神经元生存蛋白（SMN）的水平，从而促进外显子7的纳入并生成全长SMN2 转录本^[1]。

Nusinersen能显著挽救 SMN∆7 小鼠的生长曲线，增强其运动功能，大幅减少 α 运动神经元的丢失，并防止脊髓性肌萎缩症（SMA）小鼠的 α 运动神经元中典型卡哈尔体（CBs）的破坏和消失。此外，Nusinersen治疗可使 SMNΔ7 小鼠中蛋白质合成机制和聚腺苷酸化信使核糖核酸（mRNA）的分布恢复正常 ^[2]。对第一组兔子以 1.8 mg/kg的剂量鞘内（IT）推注给予Nusinersen，对第二组兔子以 1 mg/kg的剂量静脉（IV）推注给药。静脉注射的血药峰浓度（C_max）、末端血药浓度 - 时间曲线下面积（AUC_last）和初始血药浓度（C₀）分别为 15.6±4.88 μg/ml、17.8±4.10h*μg/ml和 17.6±6.20μg/ml；鞘内注射的达峰时间（T_max）、血药峰浓度（C_max）和末端血药浓度 - 时间曲线下面积（AUC_last）分别为 1h、6.0±0.10μg/ml和 12.4±1.15h*μg/ml。计算得出Nusinersen的生物利用度为33%^[3]。