Academic Journal
Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes
| العنوان: | Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes |
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| المؤلفون: | Lindborg, Stacy R., Goyal, Namita A., Katz, Jonathan, Burford, Matthew, Li, Jenny, Kaspi, Haggai, Abramov, Natalie, Boulanger, Bruno, Berry, James D., Nicholson, Katharine, Mozaffar, Tahseen, Miller, Robert, Jenkins, Liberty, Baloh, Robert H., Lewis, Richard, Staff, Nathan P., Owegi, Margaret Ayo, Dagher, Bob, Blondheim‐Shraga, Netta R., Gothelf, Yael, Levy, Yossef S., Kern, Ralph, Aricha, Revital, Windebank, Anthony J., Bowser, Robert, Brown, Robert H., Cudkowicz, Merit E. |
| المساهمون: | California Institute for Regenerative Medicine, ALS Association |
| المصدر: | Muscle & Nerve ; volume 69, issue 6, page 719-729 ; ISSN 0148-639X 1097-4598 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2024 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | Introduction/Aims Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. Methods A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty‐five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale‐Revised (ALSFRS‐R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS‐R. Results We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel‐treated participants (baseline NfL, baseline latency‐associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin‐1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining ( p < .05) when disease characteristics ( p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel‐driven reductions in NfL were associated with less decline in ALSFRS‐R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). Discussion Following debamestrocel treatment, many biomarkers showed increases (anti‐inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/mus.28093 |
| الاتاحة: | http://dx.doi.org/10.1002/mus.28093 https://onlinelibrary.wiley.com/doi/pdf/10.1002/mus.28093 |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| رقم الانضمام: | edsbas.B1BCC8E6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/mus.28093 |
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