A new drug-free, minimally invasive intervention targets the root cause of progressive loss of neural function in spinal muscle atrophy (SMA), an inherited neuromuscular disease. An intervention, which involves electrical stimulation of the sensory spinal nerves, can gradually reawaken functionally silent motor neurons in the spinal cord and improve leg muscle strength and walking in adults with SMA. The findings were reported by University of Pittsburgh School of Medicine researchers in Nature Medicine today.

Early results from a pilot clinical trial in three human volunteers with SMA show that one month of regular neurostimulation sessions improved motoneuron function, reduced fatigue and improved strength and walking in all participants, regardless of the severity of their symptoms. The study is first to show that a neurotechnology can be engineered to reverse degeneration of neural circuits and rescue cell function in a human neurodegenerative disease.

To counteract neurodegeneration, we need two things – stop neuron death and restore function of surviving neurons. In this study we proposed an approach to treat the root cause of neural dysfunction, complementing existing neuroprotective treatments with a new approach that reverses nerve cell dysfunction.”

Marco Capogrosso, Ph.D., co-corresponding author, assistant professor of neurosurgery at Pitt

SMA is a genetic neurodegenerative disease that manifests in progressive death and functional decline of motor neurons — nerve cells that control movement by transmitting signals from the brain and the spinal cord to the muscles. Over time, the loss of motor neurons causes gradual muscle weakness, and leads to a variety of motor deficits, including for the participants in this trial, difficulty in walking, climbing stairs and standing up from chairs.

While there is no cure for SMA, several promising neuroprotective treatments have become available in the last decade. These include gene replacement therapies and medications, both of which stimulate the production of motoneuron-supporting proteins that prevent neuronal death and that slow down – though do not reverse – disease progression.

Studies show that movement deficits in SMA emerge before widespread motoneuron death, suggesting that underlying dysfunction in spinal nerve circuitry may contribute to disease onset and symptom development. According to earlier research on animal models of SMA by study co-author George Mentis, Ph.D., at Columbia University, surviving motor neurons receive fewer stimulation inputs from sensory nerves – fibers that return the information from skin and muscles back to the central nervous system. Compensating for this deficit in neural feedback could, therefore, improve communication between the nervous system and the muscles, aid muscle movement and combat muscle wasting.

Pitt researchers hypothesized that a targeted epidural electrical stimulation therapy could be used to rescue lost nerve cell function by amplifying sensory inputs to the motor neurons and engaging the degenerated neural circuits. These cellular changes could, in turn, translate into functional improvements in movement capacity.

The Pitt study was conducted as part of a pilot clinical trial that enrolled three adults with milder forms of SMA (Type 3 or 4 SMA). During a study period of 29 days, participants were implanted with two spinal cord stimulation (SCS) electrodes that were placed in the lower back region on each side of the spinal cord, directing the stimulation exclusively to sensory nerve roots. Testing sessions lasted four hours each and were conducted five times a week for a total of 19 sessions, until the stimulation device was explanted.

After confirming that the stimulation worked as intended and engaged spinal motor neurons, researchers performed a battery of tests to measure muscle strength and fatigue, changes in gait, range of motion and walking distance, as well as motoneuron function.

“Because SMA is a progressive disease, patients do not expect to get better as time goes on. But that is not what we saw in our study. Over the four weeks of treatment, our study participants improved in several clinical outcomes with improvements in activities of daily living. For instance, toward the end of the study, one patient reported being able to walk from their home to the lab without becoming tired,” said co-corresponding author Elvira Pirondini, Ph.D., assistant professor of physical medicine and rehabilitation at Pitt.

 All participants increased their 6-Minute Walk Test score – a measure of muscle endurance and fatigue – by at least 20 meters, compared to a mean improvement of 1.4 meters over three months of comparable exercise regimen unaided by SCS and a median increase of 20 meters after 15 months of SMA-specific neuroprotective pharmacologic therapy.

These functional gains were mirrored by improved neural function, including a boost in motoneurons’ capacity to generate electrical impulses and transmit them to the muscles.

“Our results suggest that this neurostimulation approach could be broadly applied to treat other neurodegenerative diseases beyond SMA, such as ALS or Huntington’s disease, as long as appropriate cell targets are identified in the course of future research,” said co-corresponding author Robert Friedlander, M.D., chair of neurosurgery at Pitt and co-director of the UPMC Neurological Institute. “We are hoping to continue working with SMA patients and launch another clinical trial to test the long-term efficacy and safety of electrical spinal cord stimulation.”

Genis Prat-Ortega, Ph.D., Scott Ensel, B.S., and Serena Donadio, B.S., all of Pitt, are co-first authors of the study. Other authors of the study are Amy Boos, M.S., Jacqueline Ho, M.D., Sarah Frazier-Kim, Daryl Fields, M.D., Ph.D., Lee Fisher, Ph.D., Paula Clemens, M.D., and Peter Gerszten, M.D., all of Pitt; Luigi Borda, B.S., Prakarsh Yadav, B.S., Nikhil Verma, B.S., and Douglas Weber, Ph.D., all of Carnegie Mellon University; Tina Duong, Ph.D., of Stanford University; Jacqueline Montes, P.T., Ed.D., and George Mentis, Ph.D., of Columbia University; Steven Weinstein, Mikael Eliasson, of Genentech Roche; and Karen S. Chen, of the Spinal Muscular Atrophy Foundation.

This research was supported by an exploratory research grant from F. Hoffmann–La Roche. Genentech, Inc. (a member of the Roche Group) and the University of Pittsburgh hold rights to IP related to this study. Marco Capogrosso, Genis Prat-Ortega and Mikael Eliasson hold patent applications that relate to this work.