Investigating Neuromuscular Junction defects in Spinal Muscular Atrophy following central and peripheral SMN restoration

Topic:

Clinical Trials

Poster Number: P272

Author(s):

Michael Isfort, MD, The Ohio State University Wexner Medical Center, Andrea Jaworek, PT, DPT, CLT, The Ohio State University Wexner Medical Center, Kathryn Jira, DPT, The Ohio State University Wexner Medical Center, Georgia Cinkay, BS, The Ohio State University Wexner Medical Center, Marco Tellez, CCRP, The Ohio State University Wexner Medical Center, Matti Allen, MD, PhD, University of Ottawa, Songzhu Zhao, MS, The Ohio State University, Kristina Kelly, DPT, University of Missouri, W. David Arnold, MD, University of Missouri, Bakri Elsheikh, MBBS, FRCP (Edin), The Ohio State University Medical Center

OBJECTIVE
To evaluate the impact of risdiplam on neuromuscular junction (NMJ) transmission compared to historical controls treated with nusinersen and to examine associations between physical function, mobility, and fatigue with NMJ transmission failure after at least 12 months of risdiplam treatment.

BACKGROUND
Spinal Muscular Atrophy (SMA) alters NMJ transmission. We previously found that NMJ transmission defects persist with intrathecal nusinersen treatment, suggesting peripheral SMN increases may be necessary to improve NMJ function.

DESIGN/METHODS
This proof-of-concept study included adults with 5q-SMA. Abnormal repetitive nerve stimulation (RNS) was defined as >10% decrement in compound muscle action potential (CMAP). Assessments included handheld dynamometry, SMA functional rating scale, Revised Upper Limb Module (RULM), Fatigue Severity Scale (FSS), ulnar motor unit number estimate (MUNE), CMAP, and SMUP. Ambulatory participants completed the Hammersmith Functional Motor Scale Expanded (HFMSE) and the 6-minute walk test (6MWT), while non-ambulatory participants completed the Adapted Test of Neuromuscular Disorders (ATEND).

RESULTS
Interim analysis of 14 participants (median age 31 years; range 20–46; 57% female) showed 57% had >10% RNS decrement. No significant differences in age, sex, disease duration, treatment duration, motor function, or strength were found between groups with and without abnormal RNS. RNS decrement negatively correlated with treatment duration (r = -0.57, p = 0.031), suggesting that longer treatment may be associated with reduced decrement. RNS was positively correlated with elbow flexion strength (r = 0.54, p = 0.044) but not with other strength, functional, or electrodiagnostic measures. Preliminary data showed no improvement in % RNS decrement with risdiplam compared to nusinersen.

CONCLUSIONS
NMJ transmission defects persist in adults with SMA despite risdiplam treatment. Correlations with treatment duration suggest modulation over time. This ongoing study will provide additional data to further explore these preliminary findings. Overall, the results suggest that NMJ transmission could serve as a potential target for further pharmacological intervention.

Acknowledgments:
This study was funded by Genentech, and we extend our gratitude to all the participants who contributed to this research.