Mechanisms and Treatment of Exercise Intolerance and Persistent Fatigue in Spinal Muscular Atrophy

Study Overview
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Brief Summary
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This study will focus on the pathophysiological underpinnings of reduced exercise capacity and fatigue in ambulatory patients with spinal muscular atrophy (SMA). There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to survival motor neuron (SMN) protein deficiency. This is an observational, single visit study including 34 ambulatory SMA patients treated with SMN repletion therapies (risdiplam or nusinersen) for at least 6 months at enrollment.

Detailed Description
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SMN depletion affects muscle mitochondria and thus muscle function as a result. The relationship between these and their effect(s) on fatigue in the context of SMN repletion treatment has not been evaluated. If muscle function is vulnerable to SMN insufficiency, treatment strategies targeting muscle in addition to the central nervous system (motor neurons) may ameliorate fatigue and improve exercise capacity, thereby improving quality of life and bringing SMA treatments closer to a cure. This project explores such an idea by comparing the effects of the two different SMN repletion modalities in patients. This is an observational cross-sectional study involving ambulatory SMA children and adults treated for at least 6 months with SMN repletion therapy, either (1) systemically with risdiplam, or (2) intrathecally (central nervous system-only), with nusinersen.

Official Title
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Mechanisms and Treatment of Exercise Intolerance and Persistent Fatigue in Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genetic confirmation of SMA with laboratory documentation of homozygous deletion of survival motor neuron (SMN1) exon 7; At least 8 years of age at time of signing Informed Consent Form (or assent) Children or adults currently receiving treatment, for at least 6 months, with SMN repletion therapy, either with (1) risdiplam, or (2) nusinersen Able to walk independently at least 25 meters Able to tread a stationary cycle ergometer. Exclusion Criteria: Unable to walk 25 meters independently. Use of investigational medications intended for the treatment of SMA within 30 days prior to study entry. The presence of any contraindication to exercise according the American College of Sports Medicine (ACSM) criteria.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Nusinersen treated<br>Children and adults who are currently treated with nusinersen for at least 6 months prior to enrollment. | |
| Risdiplam treated<br>Children and adults who are currently treated with risdiplam for at least 6 months prior to enrollment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak oxygen uptake | Participants will undergo an exercise tolerance test performed by a clinical exercise physiologist using an electronically-braked recumbent cycle ergometer to determine peak oxygen uptake (VO2 max). | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIRS derived index of muscle oxygen extraction | Near Infrared Spectroscopy (NIRS) is a simple, non-invasive method to measure oxygen in muscle and other tissues in vivo. | Baseline | 
| Distance walked during the Six Minute Walk Test (6MWT) | 6MWT is an objective evaluation of functional exercise capacity, measures the maximum distance a person can walk in six minutes over a 25-meter linear course. | Baseline | 
| Leg muscle composition | To characterize leg muscle composition, quality and architecture using MRI and ultrasound in individuals with SMA treated with agents that restore SMN either systemically (risdiplam) or to central nervous system alone (nusinersen). | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SMA, spinal muscular atrophy, neuromuscular disease, risdiplam, nusinersen, aerobic capacity, oxygen uptake, fatigue, near infrared spectroscopy, muscle ultrasound, exercise tolerance, six minute walk test, mitochondria mitophagy, mitochondria, exercise, cycle ergometry