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Frontiers in Neurology

Neurodegeneration

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2018.00971

Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients

 Siw Johannesen1,  Bettina Budeus2, Sebastian Peters1, Sabine Iberl3, Anne-Louise Meyer1, Tina Kammermaier1, Eva Wirkert1, Tim-Henrik Bruun1, Verena Samara4,  Wilhelm Schulte-Mattler1, Wolfgang Herr3, Armin Schneider2, Jochen Grassinger3 and  Ulrich -. Bogdahn1*
  • 1Klinik für Neurologie, Universitätsklinikum Regensburg, Germany
  • 2lifedatascience consulting, Germany
  • 3Klinik und Poliklinik für Innere Medizin III, Universitätsklinikums Regensburg, Germany
  • 4Stanford Neuroscience Health Center, Stanford Healthcare, United States

Objective:
To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS).
Methods:
36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90 to 2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34+ and CD34+CD38- cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted.
Results:
Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF.
Conclusions:
G-CSF treatment is feasible and safe, and might be a treatment option for ALS patients. It may exert its beneficial effects through neuroprotective and –regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.

Keywords: Amyotrophic Lateral Sclerosis, Granulocyte-colony stimulating factor, Cytokines, Hematopoietic stem and progenitor cells (HSPC), Treatment

Received: 20 Sep 2018; Accepted: 29 Oct 2018.

Edited by:

Peter Bede, Trinity College Dublin, Ireland

Reviewed by:

FOTEINI CHRISTIDI, National and Kapodistrian University of Athens Medical School, Greece
Giorgia Querin, INSERM U1146 Laboratoire d'Imagerie Biomédicale, France  

Copyright: © 2018 Johannesen, Budeus, Peters, Iberl, Meyer, Kammermaier, Wirkert, Bruun, Samara, Schulte-Mattler, Herr, Schneider, Grassinger and Bogdahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Ulrich -. Bogdahn, Klinik für Neurologie, Universitätsklinikum Regensburg, Regensburg, Germany, uli.bogdahn@ukr.de