Nusinersen (Spinraza) constitutes a breakthrough treatment option for spinal muscular atrophy (SMA), which is an inherited neurodegenerative disease that leads to motor neuron degeneration. The FDA's approval of Nusinersen marked a significant advancement for gene therapy targeted at the central nervous system (CNS) conditions.
Table 1. Some oligonucleotide drugs in clinical stage or already marketed for CNS indications
| Drug | Type | Indications | Development phase | Route of administration |
| Nusinersen | ASO | Spinal Muscular Atrophy | Marketed | Intrathecal administration |
| Tofersen | ASO | Amyotrophic Lateral Sclerosis | Marketed | |
| Zilganersen | ASO | Alexander disease | Phase 3 | |
| Tominersen | ASO | Huntington's Disease | Phase 3 |
Nusinersen functions as an antisense oligonucleotide (ASO) that targets the survival motor neuron 2 (SMN2) gene to alter its splicing and thereby mitigates the progression of SMA pathology. Mutations in the SMN1 gene result in insufficient SMN protein production, which leads to SMA because this protein is essential for motor neuron survival. The SMN2 gene produces some functional SMN protein because of its high sequence similarity to SMN1. The SMN1 gene mutation leads to decreased production of SMN protein, which destroys motor neurons and causes muscle weakness with atrophy.
Figure 1. Mechanism of action of nusinersen[1].
Nusinersen works by attaching to SMN2 pre-mRNA within a splicing regulatory region called the intronic splicing silencer ISS-N1. The binding reaction blocks exon-7-skipping and enhances exon-7 incorporation, which leads to the production of complete functional SMN protein. The therapeutic approach successfully makes up for SMN1 deficiencies, which leads to better motor neuron conditions and slows down disease advancement.
Nusinersen administration requires intrathecal injection, which delivers the medication directly into the cerebrospinal fluid (CSF) through lumbar puncture. The intrathecal method remains critical for Nusinersen administration because its large molecular size and negative charge prevent it from passing through the blood-brain barrier (BBB). The BBB serves to shield the CNS from harmful toxins yet creates barriers to therapeutic agent delivery, particularly for large molecules such as oligonucleotides.
Nusinersen uses intrathecal administration to circumvent the BBB so it can access the CSF to impact motor neurons. The CSF flows through the CNS to deliver the drug directly to target areas like the spinal cord and brainstem where motor neurons reside. The extended half-life of Nusinersen within the CNS enables less frequent dosing schedules than those needed for systemic therapies. The treatment method improves patient compliance because it requires fewer injections as time goes on.
Figure 2. Nusinersen intrathecal injection process under the guidance of B-ultrasound and CT[2].
The clinical success of Nusinersen was validated through several phase 3 clinical trials such as ENDEAR, CHERISH, and SHINE. SMA patients with early-onset disease forms have shown substantial motor function and survival rate improvements alongside other clinical benefits across multiple trials.
Efficacy in Infants and Children
Nusinersen demonstrates exceptional effectiveness as a treatment option for infants experiencing SMA type 1, which represents the most severe disease manifestation. The ENDEAR trial showed that infants who received Nusinersen treatment displayed significant advancements in motor milestones such as independent sitting and head control, which untreated SMA type 1 patients generally cannot achieve. Infants who received Nusinersen treatment showed a significantly decreased risk of death or permanent ventilation dependency.
The HERISH trial demonstrated that Nusinersen treatment led to better motor functions and decelerated disease progression in SMA type 2 patients who exhibit slower progression of their condition. The treatment group patients showed improved sitting ability and gained independent mobility, which led to better quality of life.
Efficacy in Adults
The therapeutic benefits of Nusinersen have been confirmed through studies involving adult SMA patients. The clinical outcomes for adults receiving treatment show less pronounced results compared to infants but demonstrate substantial improvements in upper limb function, including handgrip strength and fine motor skills. The findings become particularly important for adults whose motor function declined progressively before starting treatment.
Figure 3. Summary of Nusinersen clinical trials[3].
Most patients tolerate Nusinersen well because its adverse events remain mild with manageable effects. Injection site reactions such as pain, erythema, and swelling, together with transient fever, respiratory infections, and headaches, are common side effects. Typically, these adverse events remain minor and resolve themselves as time passes.
The intrathecal administration of Nusinersen introduces specific risks that patients need to consider. A subset of patients who received treatment developed serious adverse events (SAEs) such as increased cerebrospinal fluid (CSF) pressure needing medical attention. Hepatic and renal dysfunction represents rare yet serious complications that become more likely with prolonged therapy.
The long-term safety profile for Nusinersen remains under investigation and requires further monitoring as additional patients receive prolonged therapy. The advantages of Nusinersen treatment surpass its potential risks when taking into account the severe consequences of not treating SMA.
The introduction of Nusinersen into SMA treatment protocols marks a significant breakthrough that brings hope to those affected by this life-threatening condition. The unique method of action through intrathecal delivery coupled with established clinical advantages positions Nusinersen as an essential treatment foundation for SMA.
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