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General Description:

Nusinersen, identified by CAS number 1258984-36-9, is a notable compound with significant therapeutic applications. An antisense oligonucleotide that induces survival motor neuron (SMN) protein expression, it was approved by the U.S. FDA in December, 2016 as Spinraza for the treatment of children and adults with spinal muscular atrophy (SMA). It is adminstrated as direct intrathecal injection.

Indications:

This drug is primarily indicated for: Indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Nusinersen undergoes metabolic processing primarily in: 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 . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Nusinersen are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Nusinersen is an important consideration for its dosing schedule: The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Nusinersen exhibits a strong affinity for binding with plasma proteins: CSF: < 25% Plasma: >94%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Nusinersen from the body primarily occurs through: Excreted by the kidney as chain-shortened oligonucleotides, which are not considered pharmacologically active. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Nusinersen is distributed throughout the body with a volume of distribution of: CSF: 0.4 L Plasma: 29 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Nusinersen is a critical factor in determining its safe and effective dosage: Slow clearance is observed. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Nusinersen exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Nusinersen functions by: Nusinersen is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. Nusinersen acts to replace the SMN protein deficit which causes SMA, by increasing the splicing efficiency of the SMN2 pre- mRNA. More specifically, nusinersen in an 18-mer 2’-MOE phosphorothioate antisense oligonucleotide that acts as a splice-altering oligonucleotide. Nusinersen was designed to pair with a specific target sequence on the SMN2 pre-mRNA to displace heterogeneous ribonucleoproteins (hnRNPs) at the intronic splice silencing site-1 (ISS-1) between exons 7 and 8 to allow for more complete translation of SMN protein from the paralogous gene SMN2. Further reinforcing this concept, SMA phenotype is closely tied to SMN2 copy number. SMN2 serves to produce SMN protein, however at a greatly reduced rate because of differential splicing caused by the binding of the hnRNPs at the ISS-1. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Nusinersen is categorized under the following therapeutic classes: Antisense Oligonucleotides, Increased Protein Synthesis, Musculo-Skeletal System, Nucleic Acids, Nucleotides, and Nucleosides, Nucleotides, Polynucleotides, Survival Motor Neuron-2-directed RNA Interaction. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.