Arguably the aspect of novel therapies for spinal muscular atrophy (SMA) that deserves the most attention is their impact on respiratory muscles—in blunt terms, whether they allow patients to continue to breathe without external support. Although progressive muscle wasting and the eventual loss of mobility are the most prominent characteristics of SMA, it is the wasting away of the respiratory muscles that eventually leads to death.
Let us first take a look at a clinical study conducted by Lavie and colleagues that studied the impact of nusinersen on respiratory function.
Natural History Observations
“Most patients with SMA1 experience the complications of respiratory deterioration in the first year of life and require various therapies to support airway clearance and ventilation,” Lavie et al wrote. “Natural history studies have shown that 100% of patients with SMA1 older than 12 months of age required nutritional or combined nutritional and ventilation support due to respiratory failure, and that 61% of patients with SMA1 required ≥1 intubation within the first year of life.”
This clearly demonstrates the profound negative effect that SMA has on respiratory function. However, novel therapies such as nusinersen have raised hopes for improved clinical outcomes. “Nusinersen, an antisense oligonucleotide designed to increase the expression of the SMN2 protein, was the first approved drug to treat all types of SMA in both the pediatric and adult populations,” the researchers noted.
Because data on respiration and nusinersen remain scarce, Lavie and colleagues sought to report their real-world experience of using nusinersen on patients with SMA. The study was conducted at Tel Aviv Sourasky Medical Center in Israel, a center that treats the majority of the country’s SMA patients. They collected data prospectively from patients with SMA type 1 who were treated with nusinersen between January 2017 and January 2020. There was no control group.
“Our aim was to describe the clinical characteristics, mainly respiratory, of these patients over a 2-year treatment period,” the study team explained.
Read more about SMA epidemiology
The researchers assessed 20 patients with SMA type 1 before and after 2 years of nusinersen treatment. Among the participants, 16 patients were already on assisted ventilation—8 invasive and 8 noninvasive.
After 2 years of treatment, the research team reported there was no change in the respiratory support used by the participants.
The 4 patients who did not need assisted ventilation at baseline all had assisted ventilation initiated during the study. In addition, 2 patients died from acute respiratory failure, 1 sustained a severe brain injury, and 4 had recurrent or chronic atelectasis.
For those hoping nusinersen would provide the magic solution to the respiratory problems in SMA, the results of this study might come as a bitter disappointment. The research team summed up their findings by saying: “There was no improvement in respiratory insufficiency or reduction in the need for assisted ventilation among any of the children.”
The only caveat here is that “from a respiratory perspective, our experience was that most patients were stable in their need for assisted ventilation and did not worsen as expected given the natural history of the disease,” but neither did “they improve as one would hope,” the authors of the study wrote.
A Proactive Approach
In another study on the respiratory impact of novel SMA therapies, Paul and colleagues reviewed the pulmonary effects of nusinersen in patients with SMA. They emphasized the importance of understanding the baseline respiratory function of SMA patients and devising treatment strategies accordingly.
“Understanding the baseline level of function at the start of treatment is essential, and pulmonary therapy regimens and ancillary support can be tailored to individual patient needs with modifications,” they wrote, identifying newborn screening as one of the best ways to detect and treat SMA early.
Read more about SMA therapies
Paul et al acknowledged that responses to novel SMA therapies such as nusinersen can be varied due to multiple factors. Regardless of the outcome, they stressed the importance of continued chest physiotherapy and a vigilant approach to ensuring optimal respiratory function.
“Despite improved strength and function of the respiratory muscles, we recommend continuing chest therapies and assisted cough clearance to prevent atelectasis and pneumonia,” they wrote.
In addition, they recommend routine immunizations, such as the seasonal influenza vaccine, should be continued, and the need for nebulized mucolytics and bronchodilators should be considered on an individual basis.
“In summary, even among the ‘treated SMA’ children, early implementation of proactive respiratory and a multidisciplinary approach remains central to care,” they explained.
Paul and colleagues have some valuable recommendations for future research involving nusinersen and other disease-modifying therapies for SMA. For example, they recommended a longer follow-up period to see if any clinical improvements are sustained over years (and not just up to an arbitrary endpoint). In addition, they recommend detailed descriptions of the respiratory effects of SMA novel treatments.
“Clinical assessment during recovery from illnesses, especially monitoring hospitalization outcomes in terms of length of stay, need for oxygen, escalation of ventilatory support, etc. and time to recover back to pre-admission baseline will be important to monitor and document,” they wrote.
It is important to acknowledge that novel therapies, such as nusinersen and risdiplam, are steps in the right direction. With future research and the refinement of these therapies, there are reasons to be optimistic that they will indeed slow down respiratory decline significantly in the future.
Lavie M, Diamant N, Cahal M, et al. Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience. Pediatr Pulmonol. 2021;56(1):291–298. doi:10.1002/ppul.25140
Paul GR, Gushue C, Koth K, Shell, R. The respiratory impact of novel therapies for spinal muscular atrophy. Pediatr Pulmonol. 2021;56(4):721–728. doi:10.1002/ppul.25135