Early Report Suggest Disease-Modifying Therapies May Halt Sleep-Related Disordered Breathing in Spinal Muscular Atrophy

Sanjeev Vithal Kothare, MD

Findings from a small-scale study of patients with spinal muscular atrophy (SMA) showed that early treatment with a disease-modifying therapy (DMT) may ultimately interrupt the development of sleep-related disordered breathing and delay the initiation of ventilatory support. Investigators concluded that additional studies are needed to further understand the relationship between these medications and sleep-related respiratory outcomes in pediatric patients with SMA type 1.¹

Presented at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, the descriptive, retrospective cohort study included 6 patients with SMA who were on a variety of DMTs. Of them, 3 exclusively received onasemnogene abeparvovec (Zolgensma; Genentech), the only approved gene therapy for SMA, in the first year of life. The other 3 patients received both nusinersen (Spinraza; Biogen) and onasemnogene abeparvovec in the first year (n = 1) of life and onasemnogene abeparvovec followed by risdiplam (Evrysdi; Genentech; n = 2).

Senior investigator Sanjeev Vithal Kothare, MD, a professor of neurology at the Zucker School of Medicine at Hofstra/Northwell, and colleagues used a Kaplan-Meier time-to-event analysis to determine the effects of DMTs on sleep-related disordered breathing and initiation of ventilatory assistance in the first year of life. Overall, 4 of the 6 patients did not receive a sleep study, as respiratory pathology was considered not a concern at follow-up visits due to preservation or improvement of motor strength.

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A critical aspect of SMA is its impact on respiratory function. As the disease progresses, respiratory muscles, in particular intercostal muscles, become increasingly affected, leading to breathing difficulties and respiratory failure. The remaining 2 patients that received polysomnograms were diagnosed with obstructive sleep apnea after the first year of life with an average Apnea-Hypopnea Index (AHI) of 4.1, average Sp02 nadir of 81.5%, and average total arousal index of 10.

To the authors knowledge, there were no other reports that have evaluated the effects of DMTs on the development of sleep-related disordered breathing in SMA. Before the development of approved treatments for SMA, patients typically received nutritional and respiratory support, but their motor function would not improve. Nusinersen, an antisense oligonucleotide, was the first to be approved, gaining market clearance in 2016. Zolgensma, an SMN1 functional replacement gene therapy, and risdiplam, an SMN2 mRNA splicing modifier, later followed, gaining FDA approval in 2019 and 2020, respectively.

A retrospective study published in Sleep Medicine in 2023 showed that children with SMA identified through newborn screening and treated with Zolgensma have reduced sleep disordered breathing over time. Eleven children were identified via newborn screen (7 with 2 copies of the SMN2 gene and 4 with 3 copies of the SMN2 gene) and received Zolgensma at a median age of 3.6 weeks. All 11 infants met criteria for sleep disordered breathing based on their first completed polysomnograms but improved over time. Three of the infants required respiratory technology and investigators found no correlation between motor scores and polysomnogram parameters.²

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REFERENCES
1. Suri C, Palladino C, Hogan K, et al. Spinal muscular atrophy 1 genetic therapies halt development of infantile onset sleep-related disordered breathing. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. ABSTRACT 0784
2. Chiang J, Xiao L, Nigro E, et al. Sleep disordered breathing in infants identified through newborn screening with spinal muscular atrophy. Sleep Med. 2023;111:161-169. doi:10.1016/j.sleep.2023.09.019.