Update on Biomarkers in Spinal Muscular Atrophy

The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. SMN2 copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. Recent therapeutic advancements in SMA have shown promising results, though there is still a great need to identify and understand the impact of biomarkers in modulating disease onset and progression.

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Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy

Brain and Development ◽

10.1016/j.braindev.2008.08.012 ◽

2009 ◽

Vol 31 (1) ◽

pp. 42-45 ◽

Cited By ~ 34

Author(s):

Mohd Shamshudin Watihayati ◽

Hayati Fatemeh ◽

Marzuki Marini ◽

Amin Baig Atif ◽

Wan Mohd Zahiruddin ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Disease Severity ◽

Copy Number ◽

Muscular Atrophy

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Faculty Opinions recommendation of Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718522863.793500172 ◽

2014 ◽

Author(s):

X William Yang ◽

Nan Wang

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Function ◽

Muscular Atrophy ◽

Improve Motor Function

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Faculty Opinions recommendation of Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718522863.793498241 ◽

2014 ◽

Author(s):

Mustafa Sahin

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Function ◽

Muscular Atrophy ◽

Improve Motor Function

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Contribution of the immune system and astrocytes to spinal muscular atrophy pathology

10.32469/10355/66066 ◽

2018 ◽

Author(s):

◽

Marie-Therese Khairallah

Keyword(s):

Immune System ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Muscular Atrophy ◽

Membrane Integrity ◽

Survival Motor Neuron ◽

White Pulp ◽

Functional Impairments ◽

Altered Expression ◽

The Impact

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and the leading genetic cause of infant mortality. SMA is caused by afunctional loss of the survival motor neuron-1 (SMN1) gene and the subsequent deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. SMA presents by motor neuron loss and muscle atrophy, and historically was considered an autonomous disease of the a-lower motor neuron (LMN). In this work we investigated effects of low levels of SMN outside the LMNs. Specifically, we looked in the spleen to determine the impact of SMN deficiency on the spleen development and the integrity of the splenic immune cells. Additionally, we analyzed astrocytes to determine if they exhibit functional impairments that could compromise their role in supporting the survival and function of LMNs. First, we reported spleen hypoplasia in multiple SMA mouse models with alteration of the splenic architecture due to a severe reduction in the red pulp zone and relative conservation of the white pulp area. We found alterations in the relative abundance of splenic mediators of the immune response, where the resident macrophage subset was depleted starting at early pre-symptomatic time (post-natal day 2), whereas the B- and T-lymphocytes, and CD11b+ macrophages had higher frequency at the late symptomatic age (post-natal day 12). Secondly, we showed that primary astrocytes derived from the spinal cord of a SMA mouse model had compromised efficiency in their glutamate uptake capacity. Moreover, SMA spinal cords had altered expression in the level of flottilin-1, a lipid raft protein necessary for cell membrane integrity and for the function of receptors and transporters. Furthermore, we showed a higher expression of the NR2B, a subunit of the glutamate receptor NMDAR that signals mainly toward apoptosis. In summary, this work characterized new pathologies in two non-neuronal tissues in the CNS and in the periphery, demonstrated that the spleen and the immune system are likely contributing to the overall clinical pathology of SMA, and found altered mechanisms in astrocytes function that might explain their effect on LMNs in SMA.

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Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition

Human Molecular Genetics ◽

10.1093/hmg/ddn357 ◽

2008 ◽

Vol 18 (2) ◽

pp. 304-317 ◽

Cited By ~ 74

Author(s):

Jan Hauke ◽

Markus Riessland ◽

Sebastian Lunke ◽

Ilker Y. Eyüpoglu ◽

Ingmar Blümcke ◽

...

Keyword(s):

Dna Methylation ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Histone Deacetylase ◽

Disease Severity ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Survival Motor Neuron Gene ◽

Histone Deacetylase Inhibition

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Cloning, Characterization, and Copy Number of the Murine Survival Motor Neuron Gene: Homolog of the Spinal Muscular Atrophy-Determining Gene

Genome Research ◽

10.1101/gr.7.4.339 ◽

1997 ◽

Vol 7 (4) ◽

pp. 339-352 ◽

Cited By ~ 76

Author(s):

Christine J. DiDonato ◽

Xiao-Ning Chen ◽

David Noya ◽

Julie R. Korenberg ◽

Joseph H. Nadeau ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Copy Number ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Survival Motor Neuron Gene

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Increased Chitotriosidase1 Concentration Following Nusinersen Treatment in Spinal Muscular Atrophy

10.21203/rs.3.rs-564501/v1 ◽

2021 ◽

Author(s):

Maren Freigang ◽

Petra Steinacker ◽

Claudia Diana Wurster ◽

Olivia Schreiber-Katz ◽

Alma Osmanovic ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Spinal Muscular Atrophy ◽

Disease Severity ◽

Antisense Oligonucleotides ◽

Muscular Atrophy ◽

Communicating Hydrocephalus ◽

Increased Risk ◽

Treatment Naïve ◽

Neuro Inflammation ◽

The Impact

Abstract BackgroundStudies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum / CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen. MethodsIn this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.ResultsCHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.ConclusionsCHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.

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