Assessment of cerebral spinal fluid biomarkers and microRNA-mediated disease mechanisms in spinal muscular atrophy patient samples.

Cerebral spinal fluid (CSF) is a promising biospecimen for the detection of central nervous system biomarkers to monitor therapeutic efficacy at the cellular level in neurological diseases. Spinal muscular atrophy (SMA) patients receiving intrathecal antisense oligonucleotide (nusinersen) therapy tend to show improved motor function, but the treatment effect on cellular health remains unknown. The objective of this study was to assess the potential of extracellular RNAs and microRNAs in SMA patient CSF as indicators of neuron and glial health following nusinersen treatment. Extracellular RNA analysis of CSF samples revealed ongoing cellular stress related to inflammation and glial differentiation, even after treatment administration. Downregulated microRNA expression associated with SMA-specific or general motor neuron dysfunction in animal and cellular models, tended to increase in nusinersen-treated patient CSF samples and correlated with SMA Type 1 and 2 motor functioning improvements. However, miR-146a, known to be upregulated in SMA-induced pluripotent stem cell (iPSC)-derived astrocytes, showed increased expression in nusinersen-treated CSF samples. We then used mRNA sequencing and multi-electrode arrays to assess the transcriptional and functional effects of miR-146a on healthy and SMA iPSC-derived motor neurons. miR-146a treatment on iPSC-derived motor neurons led to a downregulation of extracellular matrix genes associated with synaptic perineuronal net and alterations in spontaneous electrophysiological activity. Altogether, this study suggests that extracellular RNAs and microRNAs may serve as useful biomarkers to monitor cellular health during nusinersen treatment. Moreover, these data highlight the importance of addressing astrocyte health and response to nusinersen in SMA pathogenesis and treatment strategies.

Outcomes of early-treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study.

INTRODUCTION/AIMS: While prompt identification and treatment of infants with spinal muscular atrophy (SMA) can ameliorate outcomes, variability persists. This study assessed management and outcomes of early-treated infants with SMA. METHODS: We analyzed retrospective data at 12 centers on infants with SMA treated at age ≤6 weeks from August 2018 to December 2023. RESULTS: Sixty-six patients, 35 with two SMN2 copies and 31 with ≥3 SMN2 copies, were included. Twenty-five (38%, 22 with two SMN2 copies), had SMA findings before initial treatment which was onasemnogene abeparvovec in 47 (71%) and nusinersen in 19 (29%). Thirty-two received sequential or combination treatments, including 16 adding nusinersen or risdiplam due to SMA findings following onasemnogene abeparvovec. All sat independently. Compared to children with ≥3 SMN2 copies, those with two SMN2 copies were less likely to walk (23/34 [68%] vs. 31/31 [100%], p < .001) and less likely to walk on time (9/34 [26%] vs. 29/31 [94%], p < .001); one non-ambulatory child was <18 months old and was excluded from this analysis. No patients required permanent ventilation or exclusively enteral nutrition; six required nocturnal non-invasive ventilation and four utilized supplemental enteral nutrition, all with two SMN2 copies. DISCUSSION: Early treatment of infants with SMA can improve outcomes as indicated by our cohort, all of whom sat independently and are without permanent ventilation. However, our study demonstrates ongoing disability in most children with two SMN2 copies despite early monotherapy and emphasizes the need for additional research, including earlier monotherapy, initial combination therapy, prenatal treatment, and non-SMN modifying treatments.

Validity of respiratory scores in bronchiolitis.

OBJECTIVE: The primary objective of this study was to establish the validity and reliability of 2 respiratory scores, the Respiratory Distress Assessment Instrument (RDAI) and the Children's Hospital of Wisconsin Respiratory Score (CHWRS), in bronchiolitis. A secondary objective was to identify the respiratory score components that most determine overall respiratory status. METHODS: This was a prospective cohort study in infants aged < 1 year seen at Children's Hospital of Wisconsin for bronchiolitis. We evaluated: (1) discriminative validity (the score's ability to discriminate between 2 different outcomes) of the respiratory scores to identify emergency department (ED) disposition by using receiver operating characteristic curves; and (2) construct validity (the score's ability to measure what it is thought to measure, overall respiratory status) by using length of stay (LOS) as a proxy for disease severity and comparing correlations between changes in respiratory scores and LOS. Interrater reliability was established by using intraclass correlation. The contribution of individual respiratory score components to determine ED disposition was studied by using multivariate logistic regression. RESULTS: A total of 195 infants were included. The area under the receiver operating characteristic curve was 0.68 for CHWRS versus 0.51 for RDAI in predicting disposition. There was no correlation between initial respiratory scores or change in respiratory scores over the first 24 hours and LOS. Item analysis revealed that oxygen delivery, subcostal retractions, and respiratory rate were independently correlated with ED disposition. The CHWRS was more reliable than the RDAI. CONCLUSIONS: The CHWRS had modest discriminative validity in predicting ED disposition. Neither the CHWRS nor the RDAI had good construct validity. Respiratory rate, oxygen need, and presence of retractions were most useful in predicting ED disposition.