Spinal muscular atrophy (SMA) was first characterized by an Austrian physician named Guido Werdnig; he described a peculiar case of muscular weakness in two 10-month-old infant brothers. In the following years, Johan Hoffmann would describe 7 additional cases of a similar nature, while others described cases of a milder phenotype. Hence, the most severe form of SMA was initially known as “Werdnig-Hoffmann syndrome.” 

“All the cases presented had reported signs of degeneration of the anterior horn cells of the spinal cord, coupled with proximal muscle weakness that affects the axial, intercostal, and bulbar musculature,” Aslesh and Yokota wrote in Cells. 

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In the decades that followed, the phenotype of SMA, spanning across varying degrees of severity, was clarified by scientists. There were initial disagreements on whether the milder and more severe subtypes of SMA represented the same disease. The International Consortium of Spinal Muscular Atrophy was established in 1991 to create a universal classification scheme for this disease, which is still in use today. 

The molecular characteristics of SMA have also been characterized in detail in the last few decades. In the mid-1990s, scientists established that the SMN1 gene was responsible for causing the SMA phenotype and that a divergence event resulted in the formation of the human-specific SMN2 gene, which was a paralog of the SMN1 gene. 

“SMN protein, encoded by the SMN1 and SMN2 genes, is ubiquitously present in every cell of the body with various identified functions, including transcriptional regulation, telomerase regeneration, and cellular trafficking,” Aslesh and Yokota wrote. 

The SMN protein plays a significant role in the gestational and neonatal development of the neuromuscular system. The motor neurons of the spinal cord express high levels of SMN throughout life and are most susceptible to SMN loss in SMA. The SMN protein is also important for the proper function of neuromuscular junctions; studies indicate that SMN are localized in the presynaptic terminals of the neuromuscular junction and recruit and transports RNA transcripts along axons during axonogenesis. A reduction in SMN protein impairs the maturation of neuromuscular junctions and causes neurotransmission abnormalities. 

Nusinersen: The Revolution 

There has since been several new therapies used to treat SMA, with even newer ones in the pipeline. In this article, we will be focusing on nusinersen, the first antisense oligonucleotide (AON) treatment approved for SMA. 

“AONs are single-stranded, DNA-like molecules that are extensively studied to manipulate gene expression by hybridizing to mRNA-splicing factors,” Aslesh and Yokota wrote. 

In Orthopedic Reviews, Edinoff summarized the 4 main treatment strategies for the treatment of SMA in the last 2 decades: 

  • Enhancing the survival of motor neurons. 
  • Promoting muscular function. 
  • Introducing exogenous copies of the SMN1 gene. 
  • Modulation transcription of the SMN2 gene to create full-length gene products. 

Nusinersen is an AON directed towards SMN2 that treats SMA caused by deficiency in SMN proteins due to mutations in chromosome 5q. It works by inhibiting gene expression by binding to messenger RNA (mRNA), thus enhancing the production of SMN protein. 

This drug was initially tested with 28 patients between 2 and 14 years of age. They received a single intrathecal administration of the drug via lumbar puncture into their cerebrospinal fluid. Initial data indicates that the drug did not result in serious adverse events, prompting clinicians to move on to the next phase of the study. 

The next phase of the study involved 20 infants between 2 weeks and 7 months of age. They were given either 6 mg or 12 mg of the drug intrathecally on days 1, 15, 85, and 253. All patients received follow-up doses every 4 months, regardless of their date of drug administration. The researchers discovered that 16 infants who received the drug had modest improvements in their motor milestones. 

Subsequent trials confirmed both the effectiveness and the safety of the drug. A phase 3, double-blinded study involving 126 patients with SMA type 2 received 12 mg of nusinersen. During 15 months of evaluation, researchers observed a significant increase in their motor milestone scores. 

“Nusinersen is a successful treatment story because it caters to all SMA types and ameliorates muscle weakness, revives the motor neuron connection with the muscle, and addresses respiratory impairment to some extent,” Aslesh and Yokota wrote. 

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Today, nusinersen is available as an intrathecal drug that is repeatedly administered at a dose of 12 mg. Researchers now have their sights on reducing the injection frequency of the drug by attempting to administer higher nusinersen doses with less frequency. The success of this approach will significantly reduce the treatment burden for patients with SMA. 

The latest research suggests that SMA is best treated even before significant motor function loss is detected. Time is of the essence in SMA care; for patients with SMA type 1, irreversible loss of motor neurons begins perinatally, with 90% of motor units gone within the first 6 months of life. As medical researchers scale new heights in further improving outcomes in patients with SMA of all subtypes, it is important that early detection and diagnosis remain a central clinical priority. 


Aslesh T, Yokota T. Restoring SMN expression: an overview of the therapeutic developments for the treatment of spinal muscular atrophyCells. Published online January 26, 2022. doi:10.3390/cells11030417

Edinoff AN, Nguyen LH, Odisho AS, et al. The antisense oligonucleotide nusinersen for treatment of spinal muscular atrophyOrthop Rev (Pavia). Published online June 19, 2021. doi:10.52965/001c.24934