Spinal cord stimulation as a combination therapy for enhancing motor function in SMA

Neural circuits within the spinal cord are responsible for normal motor control and movement. Spinal motor neurons translate motor commands generated within the central nervous system to peripheral muscles. Motor neurons are activated by a precisely regulated pattern of synaptic activity from sensory neurons, local spinal interneurons and descending pathways from the brain. During development, synaptic activity received by motor neurons shapes their functional properties. In contrast, gene mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often result in motor system disorders. A prominent example of this situation is spinal muscular atrophy (SMA)—an inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in spinal reflexes, motor neuron loss and skeletal muscle atrophy. Our previous work has led us in uncovering that dysfunctioning sensory synapses degrade the ability of motor neurons to fire repeatedly and thus impair muscle contraction. Leveraging on modern and advanced technologies, we are aiming to stimulate electrically these dysfunctioning sensory synapses in both SMA patients and mouse models of disease. Our preliminary data provide a strong foundation for improving motor control in patients that have been treated with currently FDA-approved treatments but still exhibit impairments in mobility. To pursue further our approach, we need to develop, validate and ensure safety is met using mouse models of SMA. To this end, in Aim 1, we will demonstrate that spinal cord stimulation (SCS) restores motor function and provides behavioral benefits in SMA mice treated with a Risdiplam-like therapy. Specifically, we will investigate whether SCS improves fatigability and gait quality. Data from mice will be compared and associated with changes observed from Type 3 SMA patients who received SCS for 1 month. In Aim 2, we will investigate whether SCS improves motor neuron function in a mouse model of SMA. Specifically, we will test whether SCS - delivered via dorsal epidural implants at the L1-L3 spinal segments for one month - improves motor neuron firing by increasing the number and function of proprioceptive sensory synapses. To do so, we will use physiological and morphological assays. In Aim 3, we will establish safety and optimal dosing of spinal cord stimulation in SMA mice. To address this, we will undertake longitudinal studies in SMA mice implanted with epidural leads and subjected to SCS daily for up to 6 months at different dosing regimens. Potential toxic effects will be evaluated by combining behavioral and functional assays with molecular and morphological studies of the sensory-motor circuit. Project Number: 1R01NS142850-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: George Mentis (+1 co-PI) | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $660,613 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CN-A (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11388179