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. 2023;10(5):937-954.
doi: 10.3233/JND-230054.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

Jacqueline Glascock  1 , Basil T Darras  2 , Thomas O Crawford  3 , Charlotte J Sumner  3 , Stephen J Kolb  4   5 , Christine DiDonato  6 , Bakri Elsheikh  4 , Kelly Howell  7 , Wildon Farwell  8 , Marta Valente  8 , Marco Petrillo  8 , Jessica Tingey  1 , Jill Jarecki  1
Affiliations

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

Jacqueline Glascock et al. J Neuromuscul Dis. 2023.

Abstract

Background: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA.

Objectives: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA.

Methods: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions.

Results: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed.

Conclusions: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

Keywords: Spinal muscular atrophy (SMA); biomarker; motor neuron disease; neurofilament (NF).

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Conflict of interest statement

Thomas Crawford has served as a paid advisor, consultant, and/or speaker to commercial entities Biogen, AveXis/Novartis, Roche/Genentech, Scholar Rock Pfizer and Cytokinetics, and has received research funding/study site investigation support from Biogen, Avexis, Cytokinetics, Catalyst, and Erydel. He advises several patient organizations: Cure SMA, SMA Foundation, Muscular Dystrophy Foundation, Ataxia Telangiectasia Children’s Project.

Basil T. Darras, MD, has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies, Biogen, Pfizer, Sarepta, Vertex and Roche/Genentech; Steering Committee Chair for Roche FIREFISH and MANATEE studies and DSMB member for Amicus Inc. and Lexeo Therapeutics; he has no financial interests in these companies. BTD has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, Cure SMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc., for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from AveXis, Sarepta Pharmaceuticals, Novartis (AveXis), PTC Therapeutics, Roche, Scholar Rock, and Fibrogen. BTD has also received royalties for books and online publications from Elsevier and UpToDate, Inc.

This work was prepared while Christine J. DiDonato was employed at Ann & Robert H. Lurie Children’s Hospital and Northwestern University. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Bakri Elsheikh has received compensation for consulting from Biogen, Genentech, Argenx, and Stealth Bio-therapeutics.

Wildon R. Farwell was an employee of Biogen during the period of time this manuscript was written.

Jacqueline Glascock is an employee of Cure SMA and has no financial stake in any SMA drug or company involved in developing SMA drugs.

Kelly Howell has no conflicts to disclose.

Jill Jarecki was an employee of Cure SMA at the time of writing and is currently an employee of Biomarin.

Stephen Kolb receives grant support from Novartis and has served as a paid advisor for Novartis, Biogen and Genentech.

Marco Petrillo is a former employee at Biogen Inc. All conflict statement: Marco Petrillo has received Biogen stocks during his employment period.

Charlotte J. Sumner receives or has received grant support from Roche Ltd., Ionis Pharmaceuticals, Biogen, and Argenx and has served as a paid advisor, consultant, and/or speaker to Biogen, Ionis Pharmaceuticals, PTC Therapeutics, AveXis, Novartis, Roche/Genentech, Cytokinetics and Biomarin. All conflict statement: Charlotte J. Sumner receives grant support from Roche Ltd., Biogen, Argenx, and Actio Bio and has served as a paid advisor, consultant, and/or speaker to Biogen, Ionis Pharmaceuticals, PTC Therapeutics, AveXis, Novartis, Roche/Genentech, Cytokinetics, Sarepta, Atlanta, and Biomarin.

Jessica Tingey is an employee of Cure SMA and has no financial stake in any SMA drug or company involved in developing SMA drugs.

At the time of this work, Marta Valente was a full-time employee of and held stock/stock options in Biogen.

Figures

Fig. 1
Fig. 1
SMA Pathophysiology and Candidate Biomarkers. A number of candidate biomarkers have been proposed based on the pathophysiology of SMA. Genetic factors impacting the expression of SMN protein include SMN2 copy number and polymorphisms, the presence of modifier genes that can improve downstream neuronal and motor functions associated with SMA disease state, and gene transcription factors that affect the expression of SMN2 and other genes. Muscle presence and function can be measured through a variety of techniques including imaging, action potential and electrical response following motor nerve stimulation, and quantification of molecular factors that relate to muscle metabolism or damage. The presence of neurofilament in serum and CSF has been the subject of extensive research.
See this image and copyright information in PMC

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