First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

Genís Prat-Ortega^#^{1

2}, Scott Ensel^#^{2

3}, Serena Donadio^#^{1

2

3}, Luigi Borda^{4

5}, Amy Boos^{2

6}, Prakarsh Yadav^{4

5}, Nikhil Verma^{4

5}, Jonathan Ho^{1

2}, Erick Carranza^{2

3}, Sarah Frazier-Kim^{1

2}, Daryl P Fields^{1

2}, Lee E Fisher^{2

3

7

8}, Doug J Weber^{4

5

9}, Jeffrey Balzer¹, Tina Duong¹⁰, Steven D Weinstein¹¹, Mikael J L Eliasson¹¹, Jacqueline Montes¹², Karen S Chen¹³, Paula R Clemens⁶, Peter Gerszten¹, George Z Mentis^{14

15

16}, Elvira Pirondini^{17

18

19

20}, Robert M Friedlander²¹, Marco Capogrosso^{22

23

24}

Affiliations

¹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Mechanical engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁵ NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁹ The Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
¹⁰ Department of Neurology and Clinical Neurosciences, Stanford University, Palo Alto, CA, USA.
¹¹ Genentech Roche, San Francisco, CA, USA.
¹² Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY, USA.
¹³ Spinal Muscular Atrophy Foundation New York, New York, NY, USA.
¹⁴ Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁷ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
¹⁸ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
¹⁹ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
²⁰ Clinical and Translational Science Institute (CTSI), University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
²¹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. friedlanderr@upmc.edu.
²² Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.
²³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.
²⁴ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.

^# Contributed equally.

PMID: 39910271
DOI: 10.1038/s41591-024-03484-8

Clinical Trial

First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

Genís Prat-Ortega et al. Nat Med. 2025 Apr.

. 2025 Apr;31(4):1246-1256.

doi: 10.1038/s41591-024-03484-8. Epub 2025 Feb 5.

Authors

Affiliations

¹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Mechanical engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁵ NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁹ The Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
¹⁰ Department of Neurology and Clinical Neurosciences, Stanford University, Palo Alto, CA, USA.
¹¹ Genentech Roche, San Francisco, CA, USA.
¹² Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY, USA.
¹³ Spinal Muscular Atrophy Foundation New York, New York, NY, USA.
¹⁴ Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA.
¹⁵ Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁷ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
¹⁸ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
¹⁹ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
²⁰ Clinical and Translational Science Institute (CTSI), University of Pittsburgh, Pittsburgh, PA, USA. elvirap@pitt.edu.
²¹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. friedlanderr@upmc.edu.
²² Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.
²³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.
²⁴ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. mcapo@pitt.edu.

^# Contributed equally.

PMID: 39910271
DOI: 10.1038/s41591-024-03484-8

Abstract

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness, fatigue and early mortality. Three new therapies can slow disease progression, enabling people to survive albeit with lingering motor impairments. Indeed, weakness and fatigue are still among patients' main concerns. Here we show that epidural spinal cord stimulation (SCS) improved motoneuron function, thereby increasing strength, endurance and gait quality, in three adults with type 3 SMA. Preclinical works demonstrated that SMA motoneurons show low firing rates because of a loss of excitatory input from primary sensory afferents. In the present study, we hypothesized that correcting this loss with electrical stimulation of the sensory afferents could improve motoneuron function. To test this hypothesis, we implanted three adults with SMA with epidural electrodes over the lumbosacral spinal cord, targeting sensory axons of the legs. We delivered SCS for 4 weeks, 2 h per day during motor tasks. Our intervention led to improvements in strength (up to +180%), gait quality (mean step length: +40%) and endurance (mean change in 6-minute walk test: +26 m), paralleled by increased motoneuron firing rates. These changes persisted even when SCS was turned OFF. Notably, no adverse events related to the stimulation were reported. ClinicalTrials.gov identifier: NCT05430113 .

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Conflict of interest statement

Competing interests: This study was supported by an exploratory research grant from F. Hoffmann-La Roche to M.C., and Genentech and the University of Pittsburgh hold rights to intellectual property related to this study. M.C., G.P.O. and M.J.L.E. hold patent applications that relate to this work. The remaining authors declare no competing interests.

References

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First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

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First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

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