Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies

Eligibility Criteria

• * Genetic confirmation of SMA with homozygous deletion of SMN1 or compound heterozygous deletion/mutation of SMN1
• * Two, three, or four copies of SMN2
• * Age 5 to 20 years
• * Non-ambulatory participants: maximum function sitting or standing with support, never walked independently, still able to sit independently for 5 seconds at screening, with active ankle plantar flexion strength of at least 3 N with hand-held myometry and capable of performing repetitive maximal plantar flexion effort for 120 seconds. HFMSE score at screening between 10 and 45 points.
• * Ambulatory participants: minimum function of independent walking, able to walk unassisted a minimum of 100 meters at screening, ankle plantar flexion strength of at least 10 N with hand-held myometry and capable of performing repetitive maximal plantar flexion for 120 seconds. HFMSE score at screening between 40 and 60.
• * SMN-directed therapy inclusion:
• * Current Evrysdi prescription
• * Must have Evrysdi prescription through their treating physician but have not yet initiated treatment OR
• * Current Spinraza or Zolgensma prescription
• * For patients on Spinraza, must have been taking Spinraza for at least 12 months at screening (4 loading and 2 maintenance doses) and following the FDA-recommended dosing schedule
• * For patients on Zolgensma, must have been dosed at least one year prior to screening
• * Must have Spinraza or Zolgensma prescription through their treating physician OR
• * Changing from Spinraza or Zolgensma to Evrysdi
• * For patients on Spinraza, must have been taking Spinraza for at least 12 months at screening (4 loading and 2 maintenance doses) and following the FDA-recommended dosing schedule
• * For patients on Zolgensma, must have been dosed at least one year prior to screening
• * Must have voluntarily decided to switch therapies based on discussion with their treating physician
• * Must have Evrysdi prescription through their treating physician but have not yet initiated treatment OR
• * Have never received any SMN-directed therapies
• * Labs at screening that are abnormal and identified as clinically significant by the PI: CBC, and CMP, liver function tests (over twice the upper limit of normal), PT/PTT, urine protein of 2+ or greater.
• * Inability to perform reliably the motor function testing or the exercise testing in the MR scanner.
• * Treatment with a possible SMA-enhancing or mitochondrial-enhancing medication, unless discontinued within 3 months prior to screening: oral albuterol, hydroxyurea, phenylbutryate, valproic acid, creatine, l-carnitine, or other mitochondrial type supplement (riboflavin, lipoic acid, etc.). A daily multivitamin and Vitamin D supplement and intermittent inhaled albuterol are permitted if the dosage is unchanged during the study.
• * Need for routine non-invasive ventilation support.
• * Non-oral nutritional support, e.g., gastrostomy tube feeding.
• * Any ferrous metal implants (e.g., spinal rods) that preclude testing in a MR scanner.