The therapeutic landscape for spinal muscular atrophy (SMA) has transformed significantly with the arrival of nusinersen and onasemnogene abeparvovec gene therapy. 

SMA is a disease driven by alpha motor neuron degeneration located in the anterior horn of the spinal cord. Patients who have severe forms of the disease have significantly weak muscles within the first few weeks of life. In addition, they may be unable to sit independently or breathe normally. Respiratory distress is the most severe symptom of SMA, and patients who have been diagnosed with this condition unfortunately do not tend to live past 2 years of age. 

Read more about SMA etiology 

Continue Reading

“It is fortunate that we now have a few approaches that have resulted in FDA approval for the treatment of SMA,” Aslesh and Yokota wrote in Cells. “Here, we will focus on several approaches to restore SMN, including the use of synthetic nucleic acids called antisense oligonucleotides (AONs) for splice modulation, small molecules, and adeno-associated, vector-mediated gene replacement.” 

The Merits of Nusinersen 

Let us first discuss 1 of the most important new drugs used to treat SMA: nusinersen. It is an antisense oligonucleotide drug that gained FDA approval for use in 2016. Before its approval, the only treatment for SMA was supportive in nature. 

One of the key studies examining the suitability of nusinersen for use in patients with SMA was the EMBRACE study. The stated aim of this study was to evaluate the use of nusinersen in children with infantile- or later-onset SMA who were ineligible for other studies. 

In the first part of the study, participants (n=14) were randomized to either receive intrathecal nusinersen (12 g scaled equivalent dose) or a placebo (n=7). In the second part of the study, all patients subsequently received open-label nusinersen for approximately 24 months. 

The first part of the study was terminated early because the motor function benefits of nusinersen became undeniably clear. Participants randomized to receiving nusinersen had significantly higher motor milestone response rates compared to participants who did not. The safety profile of nusinersen also became well-established: no participants had to discontinue treatment due to adverse effects. 

“All efficacy analyses in this study were positive for participants receiving nusinersen, and were consistent with results from previous nusinersen studies in individuals treated after symptom onset,” Acsadi and colleagues wrote in Muscle & Nerve. 

The conclusion of this study was surprisingly upfront: nusinersen should be recommended as maintenance doses every 4 months among a wide population of children and infants with SMA. 

Onasemnogene Abeparvovec: Gene Therapy 

“Onasemnogene abeparvovec is the first available agent for SMA utilizing gene therapy to directly provide SMN1 gene in order to produce SMN protein,” Stevens and colleagues wrote in Annals of Pharmacotherapy.

Because of its gene-altering abilities, onasemnogene abeparvovec represents a new generation of medications that are redrawing the boundaries of what is therapeutically possible. For patients with SMA under 2 years of age who have mutations in both copies of the SMN1 gene, the Food and Drug Administration (FDA) has approved the use of onasemnogene abeparvovec as a 1 time dose. In addition, patients with SMA1 who possess 2 or 3 copies of SMN2 but are asymptomatic are also recommended to be administered this therapy as soon as possible. 

Let’s take a closer look at the pharmacology and pharmacokinetics of this drug. Onasemnogene abeparvovec makes use of a nonreplicating adeno-associated virus 9 (AAV9) in order to provide a copy of the gene encoding the human SMN protein — something that is missing in patients with SMA. This drug was designed to have a rapid onset with continuous expression, meaning that its effects last for a long time after initial administration. 

Read more about SMA treatment 

The way this drug works is rather simple: a single intravenous administration of the drug allows the AAV9 capsid vector to cross the blood-brain barrier and bring the gene to motor neuron cells located in the central nervous system. 

Stevens and colleagues wrote an interesting section in their study comparing this drug with nusinersen. Nusinersen came first, while onasemnogene abeparvovec was approved second. Their mechanisms of action could not be more different, but the end result is the same: increasing the production of SMN protein in motor neurons. 

There are no studies examining these 2 medications 1-on-1. One study analyzed the treatment effects of the 2 drugs by comparing data from 2 clinical studies; the researchers found that patients on onasmenogene abeparvovec had 100% overall survival, while patients on nusinersen had 84% survival. 

However, comparing the 2 drugs would be like comparing apples to oranges, because they are only superficially similar but work in fundamentally different ways. What is undeniable is that both drugs have brought about significant clinical benefits to patients with SMA. 

“Because of the distinct differences in pharmacology, combination therapy may be of interest,” Stevens et al wrote. 

Mirea and colleagues conducted a small study in which 7 patients with SMA type 1 received both therapies. Nevertheless, they discovered that patients who received both therapies responded equally well to patients who received monotherapy. Their conclusion was that early treatment was more important than combined therapy. 

However, would clinical trials that are better-designed involving a larger cohort of patients uncover further benefits of the combination of these 2 SMA drugs? It is undoubtedly an interesting prospect. Will this combination lead to near-curative results? Serious, detailed research will be needed for us to answer this question with certainty. 


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

Acsadi G, Crawford TO, Müller-Felber W, et al. Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE studyMuscle Nerve. Published online January 26, 2021. doi:10.1002/mus.27187

Stevens D, Claborn MK, Gildon BL, Kessler TL, Walker C. Onasemnogene abeparvovec-xioi: gene therapy for spinal muscular atrophyAnn Pharmacother. Published online March 23, 2020. doi:10.1177/1060028020914274

Mirea A, Shelby ES, Axente M, et al. Combination therapy with nusinersen and onasemnogene abeparvovec-xioi in spinal muscular atrophy type IJ Clin Med. Published online November 26, 2021. doi:10.3390/jcm10235540