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Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (V...

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Autores principales: McGrath, Michael S., Zhang, Rongzhen, Bracci, Paige M., Azhir, Ari, Forrest, Bruce D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093136/
https://www.ncbi.nlm.nih.gov/pubmed/37048104
http://dx.doi.org/10.3390/cells12071031
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author McGrath, Michael S.
Zhang, Rongzhen
Bracci, Paige M.
Azhir, Ari
Forrest, Bruce D.
author_facet McGrath, Michael S.
Zhang, Rongzhen
Bracci, Paige M.
Azhir, Ari
Forrest, Bruce D.
author_sort McGrath, Michael S.
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.
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spelling pubmed-100931362023-04-13 Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS McGrath, Michael S. Zhang, Rongzhen Bracci, Paige M. Azhir, Ari Forrest, Bruce D. Cells Article Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2–5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients. MDPI 2023-03-28 /pmc/articles/PMC10093136/ /pubmed/37048104 http://dx.doi.org/10.3390/cells12071031 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
McGrath, Michael S.
Zhang, Rongzhen
Bracci, Paige M.
Azhir, Ari
Forrest, Bruce D.
Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title_full Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title_fullStr Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title_full_unstemmed Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title_short Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS
title_sort regulation of the innate immune system as a therapeutic approach to supporting respiratory function in als
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093136/
https://www.ncbi.nlm.nih.gov/pubmed/37048104
http://dx.doi.org/10.3390/cells12071031
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