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 Cmax, AUClast and C0 of IV were 15.6±4.88μg/mL, 17.8±4.10 h*μg/mL and 17.6±6.20μg/mL; the Tmax, Cmax and AUClast 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).