Spinal muscular atrophy (SMA) is a genetic, neuromuscular disorder characterized by a loss of motor neurons in the spinal cord and lower brain stem.1 SMA is caused by a deficiency of the survival motor neuron (SMN) protein. In humans, this protein is important for many fundamental body functions, including walking, eating and even breathing independently.1 Without sufficient SMN protein, the signals between motor neurons and muscles are disrupted, resulting in muscle atrophy and weakness.1

SMA impacts individuals of all ages, from infants and children to teens and adults, and it presents a spectrum of motor and functional disabilities based on age of onset and highest motor milestone achieved: Some may never sit, some sit but never walk, and some walk but may lose that ability over time.1 Due to the degenerative nature of the disease, people with SMA will experience a decline in muscle strength throughout the course of their lives, although the rate and severity can vary. 

SMA therapies introduced in recent years have shifted the natural history of the disease, demonstrating unprecedented survival and improvement in motor function and giving the SMA community new hope. In clinical practice, there is a sense of urgency to address motor neuron loss in SMA from the first sign or even prior to symptoms.2

A biomarker could lead to personalized SMA treatment

Because the advent of SMA treatment options is so recent, people with SMA, their families and healthcare teams must confront complex decisions about treatment regimens. Measurements of SMA-related outcomes allow for a better understanding of all SMA types/subgroups of disease trajectory and for assessing response to treatment.3

Common motor function assessments are frequently used to evaluate the course of disease and effectiveness of treatment3 but because of the individual variability of the disease course, there is a need for predictive markers of disease progression and treatment response.

A biological marker, or biomarker, is an objective measure that can be used to inform diagnosis and prognosis, signal disease progression and predict or monitor response to therapy.4 In certain diseases, biomarkers are essential to help facilitate individualized treatment planning, and the identification and use of biomarkers in clinical decision-making is being explored.5

With three disease-modifying SMA therapies now available and more in clinical development, identifying an appropriate SMA biomarker is an important step to detect disease activity and understand treatment response so we can optimize outcomes for patients and preserve motor function for as long as possible.4

Neurofilaments as a potential biomarker for SMA

Neurofilaments have been proposed as potential biomarkers for neurological diseases, including SMA.6

When neurons die, neurofilaments are released into the bloodstream and cerebrospinal fluid (CSF).7,8 Higher neurofilament levels in the CSF are linked to neuron death or injury, and they have been found to be useful diagnostic markers in various neurodegenerative diseases.7

While further research is needed, neurofilament levels may serve as a noninvasive, easily accessible biomarker to monitor a person’s response to SMA therapy as soon as possible to help facilitate clinical-decision making across diagnosis, prognosis and pharmacotherapy. In addition to neurofilaments, several other potential biomarkers are being researched in SMA.9-15 One example is biological/molecular biomarkers, such as levels of SMN protein and SMN mRNA. Other research has shown that serum creatine kinase activity and serum creatinine concentration could be useful and easily accessible biomarkers for SMA.16

The use of these or other biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.

Biogen’s commitment to SMA research

Advances in research and clinical care have changed what it means to have SMA, but unmet needs remain for many people living with the disease.

Biogen is investing in ongoing research to deepen our understanding of the disease, inform treatment decisions and assess what it means to treat and live with SMA. Our research into neurofilaments and other potential biomarkers may aid in informing a more individualized treatment approach for SMA, as well as other neurodegenerative diseases. The ultimate aim of these biomarkers is to enable a personalized approach to management and facilitate a smooth and optimal pathway for the patient through their treatment journey.

I look forward to continuing our work at Biogen, in partnership with our collaborators, investigators, academic centers and patient advocacy groups, to expand our understanding of this disease and fulfill our mission to improve the lives of people with SMA, their caregivers and families.

Please visit www.Biogen.com for more information.

Marta Valente, PharmD, MBA is the Global Medical Head of Neuromuscular Diseases at Biogen, where she works to advance the understanding of SMA and the development of therapeutics that alter the natural course of the disease. 

References:

  1. National Institute of Neurological Disorders and Stroke, NIH, Spinal Muscular Atrophy fact Sheet. Available at https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spinal-Muscular-Atrophy-Fact-Sheet. Accessed March 2021.
  2. De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842-856. https://www.nmd-journal.com/article/S0960-8966(19)31127-7/fulltext.
  3. Trundell D, Le Scouiller S, Le Goff L, Gorni K, Vuillerot C. Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy. PLoS One. 2020 Sep 18;15(9):e0238786. doi: 10.1371/journal.pone.0238786. 
  4. Califf R. Biomarker definitions and their applications. Exp. Biol. Med. 2018; 243:213–221.
  5. Chen XH, Huang S, Kerr D. Biomarkers in clinical medicine. IARC Sci Publ. 2011;(163):303-22.
  6. Winter B, Guenther R, Ludolph AC, Hermann A, Otto M, Wurster CD. Neurofilaments and tau in CSF in an infant with SMA type 1 treated with nusinersen. J Neurol Neurosurg Psychiatry. 2019 Sep;90(9):1068-1069. doi: 10.1136/jnnp-2018-320033. Epub 2019 Jan 10.
  7. Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and Neurofilament Proteins in Health and Disease. Cold Spring Harb Perspect Biol. 2017 Apr 3;9(4):a018309. doi: 10.1101/cshperspect.a018309. 
  8. Khalil M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018.14(10):577-589.
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  11. Otsuki N, Arakawa R, Kaneko K, Aoki R, Arakawa M, Saito K. A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein. PLoS One. 2018 Aug 13;13(8):e0201764. doi: 10.1371/journal.pone.0201764.
  12. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, Swoboda KJ, Reyna SP, Sakonju A, Darras BT, Shell R, Kuntz N, Castro D, Parsons J, Connolly AM, Chiriboga CA, McDonald C, Burnette WB, Werner K, Thangarajh M, Shieh PB, Finanger E, Cudkowicz ME, McGovern MM, McNeil DE, Finkel R, Iannaccone ST, Kaye E, Kingsley A, Renusch SR, McGovern VL, Wang X, Zaworski PG, Prior TW, Burghes AHM, Bartlett A, Kissel JT; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017 Dec;82(6):883-891. doi: 10.1002/ana.25101. Epub 2017 Dec 8.
  13. Czech C, Tang W, Bugawan T, Mano C, Horn C, Iglesias VA, Fröhner S, Zaworski PG, Paushkin S, Chen K, Kremer T. Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls. PLoS One. 2015 Oct 15;10(10):e0139950. doi: 10.1371/journal.pone.0139950. 
  14. Wadman RI, Stam M, Jansen MD, van der Weegen Y, Wijngaarde CA, Harschnitz O, Sodaar P, Braun KP, Dooijes D, Lemmink HH, van den Berg LH, van der Pol WL. A Comparative Study of SMN Protein and mRNA in Blood and Fibroblasts in Patients with Spinal Muscular Atrophy and Healthy Controls. PLoS One. 2016 Nov 28;11(11):e0167087. doi: 10.1371/journal.pone.0167087. 
  15. Kollmer J, Hilgenfeld T, Ziegler A, Saffari A, Sam G, Hayes JM, Pietsch A, Jost M, Heiland S, Bendszus M, Wick W, Weiler M. Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy. Neurology. 2019 Aug 13;93(7):e653-e664. doi: 10.1212/WNL.0000000000007945. Epub 2019 Jul 10.
  16. Freigang M, Wurster CD, Hagenacker T, Stolte B, Weiler M, Kamm C, Schreiber-Katz O, Osmanovic A, Petri S, Kowski A, Meyer T, Koch JC, Cordts I, Deschauer M, Lingor P, Aust E, Petzold D, Ludolph AC, Falkenburger B, Hermann A, Günther R. Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment. Ann Clin Transl Neurol. 2021 Mar 31. doi: 10.1002/acn3.51340. Epub ahead of print.