Spinal muscular atrophy (SMA) is a genetic disease that destroys nerve cells in the spinal cord and brain stem. The loss of motor neurons leads to symptoms such as muscle weakness and the loss of motor function, characterizing SMA as a neuromuscular disorder.

SMA is a homozygous recessive disease, meaning that a child must receive this specific genetic mutation from both parents in order to be affected. The mutations that cause SMA are found in the survival motor neuron 1 (SMN1) gene on chromosome 5. The SMN1 gene controls the production of most SMN protein, which is necessary for the survival of motor neurons. The SMN1 gene is nonfunctional in people who have SMA.

Learn more about the causes of SMA here.

Fortunately, the SMN2 gene can partially recover the function of the missing SMN1 gene by supplementing the SMN protein levels in people diagnosed with SMA. However, the SMN2 gene does not create the same amount of functional full-length SMN protein as SMN1 due to a process called alternative splicing.

What Is Splicing?

Gene splicing is a normal process that occurs when DNA is converted into messenger RNA (mRNA) by a process called transcription. The pre-mRNA strand is composed of alternating sections called exons (regions of mRNA that can code for the formation of proteins) and introns (noncoding regions of mRNA).

The purpose of RNA splicing is to remove the introns, which do not contain information for creating proteins, through a process called translation. With the introns removed, the cell can begin to create important proteins based on the original genetic sequence.

Conversely, alternative splicing is a process that can remove both the introns and certain exons to create multiple diverse proteins from the same genetic starter sequence. This process is extremely important because it allows the DNA to be more efficient by creating a wide variety of proteins from the same sequence of genes. Alternative splicing also allows each cell type to precisely manage which genes are required for proper functioning, the proper timing of protein translation, and the amount of gene products that should be created in each cell.

Splicing of SMN1 and SMN2 Genes

Both the SMN1 and SMN2 genes undergo the process of splicing to create functional SMN protein. However, the variations in the splicing patterns of these two genes can result in the formation of vastly different levels of functional SMN protein.

SMN1 and SMN2 genes are almost identical to each other. The genetic code of these two genes only differs at five out of over 38,000 locations. One of these single nucleotide differences is located in the genetic coding region of exon 7. This specific variance in the DNA sequence of SMN2 results in alternative genetic splicing patterns, reducing the amount of functional SMN protein that is created by the cell.

Splicing in SMN1

The SMN1 pre-mRNA strand undergoes a splicing event that removes all of the introns in the sequence and links all of the exons together to form the normal full-length SMN protein. The mechanism of splicing in this case creates a fully functioning protein each time, which leads to a normal population of SMN protein in the spinal cord.

Alternative Splicing of SMN2

Unlike the SMN1 gene, each SMN2 gene only creates a small amount of functional SMN protein due to alternative splicing. Specifically, SMN2 splicing occurs at exon 7, which causes the section containing exon 7 in the pre-mRNA strand to be removed from some of the resulting mRNA that is transcribed from the SMN2 gene. The percentage of SMN mRNA with this deletion has been shown to fluctuate from 10 percent to 50 percent of all of the available SMN2 mRNA, depending on the person.

This type of alternative splicing is determined in each cell by factors called intronic cis-elements. These elements bind to the splice site, which is near the mutation located in exon 7, and recruit other splicing factors to that location. This process leads to the removal of exon 7 in the final mRNA product.

Skipping SMN2 exon 7 during the translation of SMN protein from SMN2 mRNA leads to a smaller and less stable protein. Since the majority of the SMN protein that is made from the SMN2 gene is not usable, people who do not have a functional SMN1 gene do not have enough SMN protein in their spinal cords to maintain the neuromuscular cells in their bodies.

Splicing in SMA Therapies

Improving the function of the SMN2 gene in people with SMA is the primary goal of the therapies that have been approved for SMA. In fact, two out of three currently approved SMA therapies — Spinraza (nusinersen) and Evrysdi (risdiplam) — target the splicing mechanism in motor neurons. The third treatment, Zolgensma (onasemnogene abeparvovec-xioi), is a prescription gene therapy that works by replacing the nonfunctional SMN1 gene with a new, fully functional SMN gene.

Even though there are varying degrees of severity in people diagnosed with SMA based on the number of copies of SMN2 the person has in each cell, Spinraza and Evrysdi are targeted drug treatments that prevent the splicing of exon 7, and can therefore be used for a range of SMA types.

Spinraza

Spinraza, released in 2017, was the first therapeutic approved for SMA by the U.S. Food and Drug Administration (FDA). Spinraza is used to treat SMA in people of all ages with any SMA type.

Spinraza is an antisense oligonucleotide that binds to a region of the SMN2 pre-mRNA called the intron-splicing silencer region. By remaining bound to this location on the pre-mRNA, the splicing machinery cannot access the splice site. This ultimately leads to blocking of the removal of exon 7, and promotes the formation of functional SMN protein. By avoiding the splicing of exon 7, Spinraza increases full-length SMN expression in the cell and prevents the loss of cells in the central nervous system.

Spinraza is administered by intrathecal injection at a hospital or a clinic. After the initial four-dose treatment regimen, Spinraza is given every four months.

Evrysdi

Evrysdi is the most recent FDA-approved treatment for SMA, released in 2020. Unlike Spinraza, Evrysdi is taken as an oral liquid once a day, and does not require a visit to the hospital or injections for drug administration. Evrysdi is currently approved for people with SMA types 1, 2, and 3 who are at least 2 months of age.

Evrysdi is a small molecule therapeutic called an RNA splice modifier. This new formulation not only allows for oral administration, but also leads to increased levels of SMN protein at a wider range of locations in the body when compared to Spinraza, which concentrates SMA protein in the central nervous system.

This drug works to block the splicing of SNM2 in a similar way to Spinraza. The small molecule binds to the mRNA near exon 7 and promotes the formation of functional SMN2 transcripts.

Early trials have shown that Evrysdi doubles the levels of full-length SMN protein in the blood of people living with SMA. Research in animals has shown that the levels of SMN protein in the blood are increased in a similar manner to other tissues and organs in the body, such as the brain, heart, and spinal cord. This means that a simple blood draw could potentially be used to monitor the effectiveness of Evrysdi for each individual person.

Outcomes for Targeted Splicing Therapies

Unfortunately, not all people respond the same to taking these targeted SMN2 splicing drugs. It is clear that some people have a much stronger response to the medication than others do. Future studies that examine possible biomarkers may help scientists understand why some do not have the same response strength as others and what kind of treatment may work better for them.

Fortunately, many people who have been treated with these targeted therapeutics have reached impressive accomplishments that would have been unlikely without treatment, such as standing or walking. However, the long-term prognosis of people using these treatments is still undetermined at this time due to the very recent release of the drugs.

So far, results show that treating children before symptoms develop has led to normal neuromuscular development in at least a dozen people. But it still remains to be seen whether these normal developmental milestones will continue throughout childhood.

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