Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients.

Bartłomiej Baumert,Alicja Zawiślak,Przemysław Nowacki,Bogumiła Osękowska,Anna Sobuś,Bogusław Machaliński,Monika Gołąb-Janowska,Agnieszka Meller,Edyta Paczkowska,Sławomir Milczarek,Agnieszka Wełnicka,Krzysztof Safranow,Karolina Łuczkowska,Zofia Ulańczyk,Karolina Machowska-Sempruch

doi:10.3390/ijms21031070

Bartłomiej Baumert, Alicja Zawiślak + Show 13 more

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https://doi.org/10.3390/ijms21031070

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Abstract

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin−) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin− cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease leading to gradual loss of motor neurons (MNs) and to death in approximately 3–5 years after diagnosis, mostly due to respiratory failure [1]
We previously demonstrated that intrathecal injection of autologous bone marrow-derived Lin− cells is a safe and feasible method aimed at trophic provision in ALS patients [23]
We evaluated correlations between clinical outcome in ALS patients after Lin− cells intrathecal administration and plasma/cerebrospinal fluid (CSF) levels of neurotrophins and C-reactive protein (CRP) at various time points after cells injection

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease leading to gradual loss of motor neurons (MNs) and to death in approximately 3–5 years after diagnosis, mostly due to respiratory failure [1]. It was first described in 1869 by Jean-Martin Charcot—one of the world’s pioneers of neurology [2]. His initial statements that the disease was never inherited and affected only motor neuron were found false in the 20th century when it was described that, in some patients, the cognitive impairment occurs together with muscle weakening, and in about 10% of cases, the disease affects members of the same family [3,4]. It is suggested that degeneration of these cells may be a consequence of an ongoing autoimmune process or related to increased inflammatory response [13,14]

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