Toward therapeutic trials in primary lateral sclerosis

Erica Scirocco¹, Matti D Allen^{2

3}, Elisa Giacomelli¹, Senda Ajroud-Driss⁴, Jinsy Andrews⁵, Sandra Banack⁶, Peter Bede^{7

8}, Michael Benatar⁹, Ken Cheung¹⁰, Philippe Corcia¹¹, Mamede de Carvalho¹², Lauren Elman¹³, John K Fink¹⁴, Angela Genge³, Orla Hardiman¹⁵, Matthew Harms⁵, Daragh Heitzman¹⁶, Grace Jang⁵, Osamu Kano¹⁷, Matthew C Kiernan¹⁸, Ikjae Lee⁵, Albert Ludolph¹⁹, Paul Mehta²⁰, Hande Ozdinler⁴, Kourosh Rezania²¹, Paride Schito²², Alexander V Sherman¹, Vincenzo Silani^{23

24}, Eric Sorenson²⁵, Martin R Turner²⁶, Leonard Van Den Berg²⁷, Hiroshi Mitsumoto⁵, Sabrina Paganoni^{1

28}

Affiliations

¹ Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Ottawa Hospital Research Institute, Ottawa, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
⁴ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁵ Neurological Institute of New York, Columbia University, New York, NY, USA.
⁶ Brain Chemistry Labs, Jackson, WY, USA.
⁷ Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁸ Department of Neurology, St James's Hospital, Dublin, Ireland.
⁹ Department of Neurology and ALS Center, University of Miami, Miami, FL, USA.
¹⁰ Mailman School of Public Health, Columbia University, New York, NY, USA.
¹¹ Department of Neurology, ALS Centre, CHRU Bretonneau, Tours, France.
¹² Department of Neurosciences and Mental Health, ULS Santa Maria, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
¹⁶ Texas Neurology, Dallas, TX, USA.
¹⁷ Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan.
¹⁸ Neuroscience Research Australia, University of New South Wales, Sydney, Australia.
¹⁹ Department of Neurology, University of Ulm, Ulm, Germany.
²⁰ Office of Innovation and Analytics, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA, USA.
²¹ Department of Neurology, University of Chicago, Chicago, IL, USA.
²² Experimental Neuropathology Unit, Division of Neuroscience, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²³ Department of Neurology & Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milano, Italy.
²⁴ Department of Pathophysiology & Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.
²⁵ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²⁷ Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands, and.
²⁸ Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 40618376
DOI: 10.1080/21678421.2025.2527123

Free article

Review

Toward therapeutic trials in primary lateral sclerosis

Erica Scirocco et al. Amyotroph Lateral Scler Frontotemporal Degener. 2025.

Free article

. 2025 Jul 6:1-8.

doi: 10.1080/21678421.2025.2527123. Online ahead of print.

Authors

Affiliations

¹ Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Ottawa Hospital Research Institute, Ottawa, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
⁴ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁵ Neurological Institute of New York, Columbia University, New York, NY, USA.
⁶ Brain Chemistry Labs, Jackson, WY, USA.
⁷ Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁸ Department of Neurology, St James's Hospital, Dublin, Ireland.
⁹ Department of Neurology and ALS Center, University of Miami, Miami, FL, USA.
¹⁰ Mailman School of Public Health, Columbia University, New York, NY, USA.
¹¹ Department of Neurology, ALS Centre, CHRU Bretonneau, Tours, France.
¹² Department of Neurosciences and Mental Health, ULS Santa Maria, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
¹⁶ Texas Neurology, Dallas, TX, USA.
¹⁷ Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan.
¹⁸ Neuroscience Research Australia, University of New South Wales, Sydney, Australia.
¹⁹ Department of Neurology, University of Ulm, Ulm, Germany.
²⁰ Office of Innovation and Analytics, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA, USA.
²¹ Department of Neurology, University of Chicago, Chicago, IL, USA.
²² Experimental Neuropathology Unit, Division of Neuroscience, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²³ Department of Neurology & Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milano, Italy.
²⁴ Department of Pathophysiology & Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.
²⁵ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²⁷ Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands, and.
²⁸ Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 40618376
DOI: 10.1080/21678421.2025.2527123

Abstract

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.

Keywords: Primary lateral sclerosis; biomarkers; clinical trials; motor neuron disease; outcome measures.

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Toward therapeutic trials in primary lateral sclerosis

Affiliations

Toward therapeutic trials in primary lateral sclerosis

Authors

Affiliations

Abstract

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