Sequence 1140(ASO-10-27 , ASO1027)
|Sequence ASO-10-27, ASO1027, ISIS 396443, ISIS-SMNRx , IONIS-SMNRx, Nusinersen, Spinraza|
|Target||SMN2 ( Homo sapiens )|
|Description|| Survival of motor neuron 2 , centromeric
Ensembl: ENSG00000205571 UniGene: Hs.202179 EntrezGene: 6607 Ensembl Chr5: 69381106 - 69409175 Strand: 1 GO terms: 0000245 0003676 0003723 0005515 0005634 0005681 0005737 0006397 0008380 0015030
|Design||MOE antisense oligonucleotide|
|Name||ASO-10-27, ASO1027, ISIS 396443, ISIS-SMNRx , IONIS-SMNRx, Nusinersen, Spinraza|
Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR. Nature. 2011 Oct 5;478(7367):123-6.PubMed: 21979052
Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed: 26823478 Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478
2’-O-(2-methoxyethyl) phosphorothioate antisense oligonucleotide ( UCACUUUCAUAAUGCUGG ) that induces survival motor neuron (SMN) protein expression. It is administrated as direct intrathecal injection of 5mL at 2.4 mg/mL.
Nusinersen (Spinraza) was approved for the treatment of spinal muscular atrophy (SMA). In clinical trials, the drug halted the disease progression in around 60% of infants affected by type 1 spinal muscular atrophy, the drug also significantly improved motor function.
Mechanism of action of Nusinersen (Spinraza):
Nusinersen target an hnRNP-A1/A2–dependent splicing silencer, ISS-N1, in intron 7 of the SMN pre-mRNA. Nusinersen displaces hnRNP proteins from the ISS-N1 site on the SMN2 pre-mRNA, facilitating accurate splicing of SMN2 transcripts (e.g., increasing the synthesis of transcripts containing exon 7) and resulting in increased production of full-length SMN protein.
Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants. Cardiac Electrophysiology: In 121 patients with spinal muscular atrophy who received either nusinersen or sham-control, QTcF values >500 ms and change from baseline values >60 ms were observed in 5% of patients receiving nusinersen. Compared to the sham-control, there was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization in patients treated with nusinersen.
Intrathecal injection of nusinersen into the cerebrospinal fluid (CSF) allows it to be distributed from the CSF to the target central nervous system (CNS) tissues. Following intrathecal administration, trough plasma concentrations of nusinersen were relatively low, compared to the trough CSF concentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours. Mean plasma Cmax and AUC values increased approximately dose-proportionally up to a dose of 12 mg.
Volume of distribution CSF: 0.4 L Plasma: 29 L
Protein binding CSF: < 25% Plasma: >94%
Nusinersen is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis primarily at the 3' end of the oligonucleotide. It is not a substrate for, or inhibitor or inducer of CYP450 enzymes. N-1 metabolites of the drug can be detected in the cerebrospinal fluid while N-1,2,3 metabolites can be predominantly detected in the plasma .
Route of elimination:
Excreted by the kidney as chain-shortened oligonucleotides, which are not considered pharmacologically active.
The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma.
Patents and estimated expiring date:
US8980853 (2030-11-24), US9717750 (2030-06-17), US8361977 (2030-05-27), US7838657 (2027-07-11), US8110560 (2025-12-05), US7101993 (2023-09-05), US6210892 (2018-10-07), US6166197 (2017-12-26).