Sometimes when the frustration of caring for an unwell patient becomes overwhelming, one wishes that they could reach into the patient’s body by way of miraculous intervention and remove the root cause of the illness. 

The fascinating thing about where we are in medicine is that the idea of curing an illness by removing its core cause no longer remains in the realm of the supernatural; instead, medical advancements mean that it is now possible to do so in a purely scientific way. By this, I refer to gene therapy, a novel method of treating diseases that allows defective genes to be removed or fixed. 

A team of Polish researchers documented the role of alternative splicing in new therapies for spinal muscular atrophy (SMA) and published their work in Genes. We will look at their findings in closer detail in this article, together with work by a group of Chinese researchers on the same theme published in Molecules and Cells. 

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Spinal Muscular Atrophy Genetics

Let us first recount a few basic facts about the genetics of SMA. It is an autosomal recessive disorder that is one of the most common causes of infant mortality in both the United States and Western Europe. Patients tend to be intellectually normal but have severe difficulties in muscle-related functions including movement, swallowing, and breathing, with the inability to breathe being the main cause of death in SMA patients. 

There are 2 nearly identical survival motor neuron (SMN) genes, both of which consist of 10 exons. According to Zhou et al, SMN protein has the following functions in mammals: 

  • Interacts with many cellular proteins and helps in assembling massive macromolecular ribonucleoprotein particle complexes
  • Functions as an antiapoptotic chaperone protein in SMN/stress granules by stabilizing RNA/protein species against stress-induced apoptosis
  • Transports specific messenger RNAs (mRNAs) to neuron neurites in neuronal RNA granules

The most severe type of SMA is SMA type I, which usually results in death before 2 years of age. Patients with SMA type II usually become wheelchair-bound at an early age and die before the age of 20. Patients with SMA types III and IV experience the mildest phenotype and may have a normal lifespan, although some still become wheelchair-bound.

SMN1 vs SMN2

So what makes the 2 nearly identical SMN genes different? According to Lejman et al, “The key difference between these genes lies in the splicing of exon 7.” Exon 7 is critically important for SMN stability, and any changes to it through omission or mutation will cause problems for normal skeletal muscular growth. 

In the SMN1 gene, mutations and deletions are the major causes of SMA development. As for the SMN2 gene, exon 7 is often skipped due to alternative splicing, which results in an unstable SMNΔ7 protein. In summary, SMA manifests when SMN1 is mutated or deleted or when SMN2 undergoes alternative splicing of exon 7.

Read more about SMA epidemiology

According to Zhou et al, “the difference in splicing between SMN1 and SMN2 plays a critical role in how SMA disease develops, progresses, and is ultimately defined,” and this is the reason why “exon 7 splicing in SMN genes has been extensively studied.” Many medical researchers studying SMA are focusing their attention on targeting the mechanisms that regulate exon 7 splicing in a way that yields therapeutic benefits. In mouse models, the restoration of exon 7 inclusion has demonstrated therapeutic benefits.

One of the more commonly accepted therapies for this purpose is antisense oligonucleotides (ASOs). How do they work? They primarily influence transcript splicing or inactivation, causing changes in the exon content. The Polish research team wrote, “Modified sequence-dependent ASOs can appropriately lead to the exclusion or inclusion of an exon that would have been excised, as is the case in SMA.” 

The First Approved ASO 

Let’s take a closer look at the first ASO approved for SMA treatment: nusinersen. It binds to the splicing inhibitory sequence of intron 7, ultimately leading to the incorporation of exon 7 into the SMN2 transcript and resulting in higher levels of fully functional SMN protein in the body. This, in turn, stops SMA disease progression by interrupting the degeneration of motor neurons. 

Read more about SMA therapies

Studies have shown that nusinersen can significantly improve the condition of treated patients. Zhou et al quoted research that demonstrated how the administration of an ASO to SMA neonate mouse models spared them from developing severe SMA and extended their median lifespan by 25-fold.

The Work Ahead 

In addition to the efforts to develop new therapeutics for SMA, medical researchers are also identifying ways in which SMA can be detected and subsequently treated early since studies have shown that this is an effective way to contain the disease. 

The success of ASOs has encouraged medical researchers to continue looking for new targetable biomarkers to halt the disease progression of SMA. According to Lejman et al, medical research is underway to move past the current paradigm of either replacing the SMN1 gene or altering SMN2 splicing; instead, medical researchers are attempting to create drugs completely independent of SMN. For example, drug types such as myostatin inhibitors, nerve connection stabilizers, or activators of muscle function may yet prove to have neuroprotective effects that significantly improve the clinical conditions of patients with SMA. 


Lejman J, Zieliński G, Gawda P, Lejman M. Alternative splicing role in new therapies of spinal muscular atrophyGenes (Basel). 2021;12(9):1346. doi:10.3390/genes12091346

Zhou J, Zheng X, Shen H. Targeting RNA-splicing for SMA treatmentMol Cells. 2012;33(3):223-228. doi:10.1007/s10059-012-0005-6