Biomarkers in Rare Disorders: The Experience with Spinal Muscular Atrophy

Tiziano, Francesco Danilo; Neri, Giovanni; Brahe, Cristina Beate

doi:10.3390/ijms12010024

Cited by 13 publications

(8 citation statements)

References 58 publications

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“…Molecular biomarkers are valuable complements to clinical SMA motor outcome measures that are subject to age limitations and motivation for performance [10]. Also, while several SMN-based pharmacodynamic (PD) biomarkers for SMA exist, not all trials will test SMN-upregulating drugs, and other non-SMN markers would be needed [21], [25], [33]. In addition, not all therapeutic interventions will be delivered systemically, and use of a biomarker matrix like plasma that reflects proteins from a number of sites may provide additional insights over measures based in blood cells [33].…”

Section: Discussionmentioning

confidence: 99%

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

et al. 2013

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ObjectivesSpinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).MethodsBforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.Results12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.ConclusionsDiscovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

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Section: Discussionmentioning

confidence: 99%

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

et al. 2013

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“…The experiments reported here examine the factors affecting SMN protein signal variability in a peripherally accessible cell matrix that is expected to be a critical pharmacodynamic biomarker for imminent or ongoing drug trials for SMA [15], [31], [32]. PBMCs have been harvested and utilized effectively to evaluate target engagement and cellular efficacy in numerous international multi-center clinical trials, most notably in the human immunodeficiency virus (HIV) field [27]–[29], [33].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Peripheral Blood Mononuclear Cell Processing and Analysis for Survival Motor Neuron Protein

et al. 2012

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ObjectivesSurvival Motor Neuron (SMN) protein levels may become key pharmacodynamic (PD) markers in spinal muscular atrophy (SMA) clinical trials. SMN protein in peripheral blood mononuclear cells (PBMCs) can be quantified for trials using an enzyme-linked immunosorbent assay (ELISA). We developed protocols to collect, process, store and analyze these samples in a standardized manner for SMA clinical studies, and to understand the impact of age and intraindividual variability over time on PBMC SMN signal.MethodsSeveral variables affecting SMN protein signal were evaluated using an ELISA. Samples were from healthy adults, adult with respiratory infections, SMA patients, and adult SMA carriers.ResultsDelaying PBMCs processing by 45 min, 2 hr or 24 hr after collection or isolation allows sensitive detection of SMN levels and high cell viability (>90%). SMN levels from PBMCs isolated by EDTA tubes/Lymphoprep gradient are stable with processing delays and have greater signal compared to CPT-collected samples. SMN signal in healthy individuals varies up to 8x when collected at intervals up to 1 month. SMN signals from individuals with respiratory infections show 3–5x changes, driven largely by the CD14 fraction. SMN signal in PBMC frozen lysates are relatively stable for up to 6 months. Cross-sectional analysis of PBMCs from SMA patients and carriers suggest SMN protein levels decline with age.ConclusionsThe sources of SMN signal variability in PBMCs need to be considered in the design and of SMA clinical trials, and interpreted in light of recent medical history. Improved normalization to DNA or PBMC subcellular fractions may mitigate signal variability and should be explored in SMA patients.

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“…Several attempts have been made to identify quantitative and clinically meaningful biomarkers for SMA, including magnetic resonance imaging (MRI), electrophysiological, protein, and molecular measures . Nevertheless, no general consensus has been reached on the most feasible ones.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal characterization of biomarkers for spinal muscular atrophy

Bonati

Holiga

Hellbach

et al. 2017

Ann Clin Transl Neurol

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ObjectiveRecent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression.Methods18 SMA patients and 19 healthy volunteers (HV) were followed in this 52‐weeks observational study. Quantitative‐MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow‐up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow‐up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations.Results QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year.InterpretationWe probed a variety of quantitative measures for SMA in a slowly‐progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease‐modifying therapies.

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Biomarkers in Rare Disorders: The Experience with Spinal Muscular Atrophy

Cited by 13 publications

References 58 publications

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Evaluation of Peripheral Blood Mononuclear Cell Processing and Analysis for Survival Motor Neuron Protein

Longitudinal characterization of biomarkers for spinal muscular atrophy

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