Use of biomarkers in ALS drug development and clinical trials

Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert

doi:10.1016/j.brainres.2014.10.031

Cited by 39 publications

(26 citation statements)

References 134 publications

(150 reference statements)

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“…Direct infusion of Actemra into patients has been shown to decrease mRNA expression of many inflammatory cytokines in the serum of patients with sALS with high basal inflammation both acutely and longitudinally, and this correlated with attenuated decrease in ALSFRS-R scores [161]. Further studies utilizing Actemra in phase II clinical trials is already planned and will need to be performed in order to validate fully its effects [167]. Prior studies identified up to a 10-fold increase in the prostaglandin E2 levels in the CSF of patients with ALS as compared with healthy control patients [51,52].…”

Section: Clinical Applicationsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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Section: Clinical Applicationsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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“…Pharmacodynamic biomarkers to evaluate disease progression and response to therapy are needed for studies in motor neuron diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) for both preclinical animal testing and in human clinical trials (1,2). Effective biomarkers could offer greater sensitivity to drug effects than standard outcomes measures such as the ALS Functional Rating Scale-Revised, strength testing, timed functional tests (such as the 6-minute walk) and forced vital capacity.…”

Section: Introductionmentioning

confidence: 99%

Single and modeled multifrequency electrical impedance myography parameters and their relationship to force production in the ALS SOD1G93A mouse

Pacheck

Sanchez

et al. 2016

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Objective The relationship between muscle force production in ALS SOD1G93A mice and single and modeled multifrequency electrical impedance myography (EIM) parameters is unknown. We evaluated the relationship between multifrequency EIM data and paw grip and in situ force measurements, as well to standard measures in including body weight and compound motor action potential (CMAP) amplitude. Methods Twenty-nine SOD1 G93A mice aged 13-18 weeks (approximately 4-5 per week) and a group of similarly aged wild-type mice (N=7) were studied with single and multifrequency EIM, CMAP, front and hind-limb paw grip measures, and in situ force measurements of the gastrocnemius. Results Significant differences among WT, presymptomatic, and symptomatic ALS animals were identified for all standard measures and single 50 kHz frequency EIM parameters. Of the modeled multifrequency measures, the center frequency, fc, an index of cell size, showed the strongest relationship to force output. The two other multifrequency parameters corresponding to cell size distribution and cell density showed consistent although mostly non-significant differences. Conclusion Reductions in force are reflected in single 50 kHz impedance values and in the fc. These data support the construct validity of EIM as an assessment tool of muscle dysfunction in diseases associated with motor neuron loss.

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“…Utilizing a combination of multiple anti-TDP-43 scFvs may prove valuable in providing a personalized diagnosis for each patient in both sporadic and familial ALS cases. A personalized blood-based diagnosis system could also be very helpful for initiating and monitoring treatment strategies for ALS [41, 42]. …”

Section: Discussionmentioning

confidence: 99%

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

et al. 2017

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BackgroundTDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples.ResultsWe developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases.ConclusionsThese results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker profile with potential to distinguish different TDP-43 pathologies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0334-7) contains supplementary material, which is available to authorized users.

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Use of biomarkers in ALS drug development and clinical trials

Cited by 39 publications

References 134 publications

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Single and modeled multifrequency electrical impedance myography parameters and their relationship to force production in the ALS SOD1G93A mouse

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

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