A breakthrough effect of gene replacement therapy on respiratory outcomes in children with spinal muscular atrophy

Abstract

Introduction Spinal muscular atrophy (SMA) is an inherited progressive neuromuscular disorder characterized by generalized hypotonia, respiratory failure and early death. The introduction of gene replacement therapy (GRT) modified the natural history of the disease. However, more data is needed to understand the long‐term effect of GRT on measurable respiratory outcomes. We report the respiratory outcomes in our cohort of patients with SMA post‐GRT in 2‐year period. Methods A retrospective chart‐review of genetically confirmed children with SMA who received GRT between 2019 and 2021 in Qatar. The evaluated respiratory outcomes were chronic respiratory support, respiratory hospitalizations, escalation of respiratory support and polysomnography results before and after GRT. Nonrespiratory outcomes; nutritional status, swallowing, and motor functions; were also assessed. Results A total of 11 patients (9 patients with SMA‐1 and 2 patients with SMA‐2) received GRT at a median age of 12 months and 22 months in patients with SMA‐1 and SMA‐2, respectively. All patients were successfully weaned off Noninvasive ventilation (NIV) except one patient who remained on mechanical ventilation through tracheostomy tube. The annualized hospitalization rate dropped by half after GRT. The average length of stay (LOS) in intensive care unit (ICU) decreased by 17.32 days/patient/year after GRT. Duration of required escalation of respiratory support during acute hospitalizations has dropped by 18.56 days/patient/year post‐GRT. Conclusion We report favorable respiratory outcomes of GRT in our cohort. GRT resulted in discontinuation of chronic respiratory support in majority of ventilated patients. GRT also resulted in decreased respiratory hospitalization rate, hospital‐LOS, ICU‐LOS, and need for escalation of ventilatory support.

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…These real-world studies have confirmed the efficacy of the gene replacement therapy in an expanded age range of patients eligible for treatment, including those up to two years old and also patients with three copies of SMN2 , regardless of the type of SMA. 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 Additionally, some studies have evaluated the use of onasemnogene abeparvovec in patients who had previously been treated with other specific therapies, such as nusinersen or risdiplam. 102 103 105 106 108 …”

Respiratory failure in a patient with VACTERL association and concomitant spinal muscular atrophy

“…While some authors report improvement of respiratory status including sleep disordered breathing in some children with SMA treated with nusinersen, 16 a more recent observational study did not find that respiratory status improved with this treatment 17 . A small case series reported favorable respiratory outcomes in patients treated with onasemnogene aboparvovec 18 . Respiratory outcomes were secondary outcomes in the original risdiplam trial, and no further reports have been published specifically regarding the impact of this treatment on respiratory function.…”

“…17 A small case series reported favorable respiratory outcomes in patients treated with onasemnogene aboparvovec. 18 Respiratory outcomes were secondary outcomes in the original risdiplam trial, and no further reports have been published specifically regarding the impact of this treatment on respiratory function.…”

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

“…51 Another retrospective study of 9 patients with SMA type 1 and 2 patients with SMA type 2 showed successful weaning of NIPPV in 10 patients after AAV9-SMN1, as well as reduced length of stay and required escalation of respiratory support during hospitalization. 52 Risdiplam is the latest FDA novel therapy approved for SMA. It was approved in August 2020 for the treatment of patients with SMA with age greater than 2 months and it is currently approved for presymptomatic infants < 2 months of age.…”

“…Importantly, there was no correlation between age at treatment, neuromotor improvement as measured by the Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP‐Intend) score and AHI, highlighting the need for other outcome measures and long term monitoring of these children 51 . Another retrospective study of 9 patients with SMA type 1 and 2 patients with SMA type 2 showed successful weaning of NIPPV in 10 patients after AAV9‐SMN1, as well as reduced length of stay and required escalation of respiratory support during hospitalization 52 …”