exploring the physiologic, pharmacodynamic, and clinical responses of skeletal muscle in patients with spinal muscular atrophy treated with smn-directed therapies

Conditions: Spinal Muscular Atrophy

Summary: in this observational study, researchers are looking at the effects of spinal muscular atrophy (sma) drugs on the muscles and nerve cells in patients with sma. primary objectives * to evaluate the feasibility and reliability of performing mr functional imaging in exercising muscle in patients with sma. * to evaluate patients with sma types 2 and 3 at baseline and longitudinally at 6 and 12 months secondary objectives * to describe the mr functional bioenergetics response in the leg muscles in four potential groups of patients with spinal muscular atrophy: untreated, actively treated with nusinersen (spinraza®) or onasemnogene abeparvovec (zolgensma®), actively treated with risdiplam (evrysdi®), and switching from spinraza or zolgensma to evrysdi. * to identify changes in motor function in patients with sma types 2 and 3 who initiate treatment with risdiplam. * to obtain biomarkers in blood, urine, and muscle tissue to provide evidence for risdiplam effect on skeletal muscle. * to obtain quality of life and disability data from participants in this study.

this is an observational study to demonstrate the feasibility of performing mr functional imaging in exercising muscle in patients with sma. the participants will be prescribed medication by their treating physician, they will not receive any drug as part of this study. participants participating in the ml43225 study, will be put into one of four groups depending on their type of sma and the drugs they may or may not be taking. they will be asked to come to clinic 3 times over one year. each visit will include magnetic resonance (mr) studies, a muscle ultrasound, a nerve test, muscle function testing, lung function testing, blood work, vital signs, and participants will be asked about their quality of life and daily life activities. after participants have completed the 3 required visits, they will be taken off study.

Eligibility criteria:
inclusion 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 exclusion criteria: * 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.

Keywords: spinal muscular atrophy (sma) sma drugs responses of skeletal muscle smn-directed therapies eyrysdi spinraza zolgensma