Nusinersen is a chemically modified antisense oligonucleotide (ASO) designed to target the survival motor neuron 2 (SMN2) pre-mRNA. It is a synthetic 18-nucleotide oligonucleotide containing 2′-O-(2-methoxyethyl) modifications and phosphorothioate linkages. Nusinersen is marketed as the sodium salt and is the active pharmaceutical ingredient of Spinraza.
Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript. This modifies SMN2 pre-mRNA splicing and increases inclusion of exon 7, resulting in increased production of full-length survival motor neuron (SMN) protein.
Nusinersen is a fully modified antisense oligonucleotide. Its structure contains phosphorothioate linkages and 2′-O-(2-methoxyethyl) substitutions on the ribofuranosyl groups. The marketed sodium salt has a reported molecular weight of 7501.0 daltons.
The CAS Registry Number for nusinersen is 1258984-36-9. PubChem and FDA substance-registration information identify nusinersen as an antisense oligonucleotide and SMN2-directed RNA-interacting substance.
Nusinersen is used as a drug substance for pharmaceutical development and manufacture of antisense oligonucleotide products targeting SMN2 pre-mRNA.
The active oligonucleotide is designed to promote exon 7 inclusion in SMN2 messenger RNA, thereby increasing production of full-length SMN protein. This mechanism is relevant to the treatment of spinal muscular atrophy (SMA).
Nusinersen is commonly represented as its sodium salt for pharmaceutical use. The current SPINRAZA labeling identifies the molecular formula as C234H323N61O128P17S17Na17 and molecular weight as 7501.0 daltons.
As an antisense oligonucleotide, nusinersen requires analytical controls that differ from conventional small-molecule APIs. Regulatory documentation identifies important active-substance quality attributes including:
The EMA assessment specifically notes that the active-substance specification for nusinersen includes controls for oligonucleotide impurities and other quality attributes.
Modern analytical methods for nusinersen include ion-pair RP-HPLC, LC-MS and other chromatographic/mass-spectrometric techniques for monitoring full-length product and related oligonucleotide impurities.
| Parameter | Specification |
|---|---|
| Appearance | White crystalline powder or crystals |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Melting Point | 150°C – 154°C |