Abstract
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) treated on a named patient basis.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 90-2160 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 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a life threatening neurodegenerative disorder characterized by premature loss of upper and lower motoneurons in the adult brain and spinal cord [1]
We investigated whether the number of mobilized hematopoietic stem cells is different in Granulocyte-colony stimulating factor (G-cerebrospinal fluid (CSF)) treated ALS patients of longer versus shorter survival
Treatment with G-CSF was offered to 36 patients seen at the University of Regensburg with definite or probable ALS according to the revised El Escorial criteria [28]
Summary
Amyotrophic lateral sclerosis (ALS) is a life threatening neurodegenerative disorder characterized by premature loss of upper and lower motoneurons in the adult brain and spinal cord [1]. The life time risk of ALS is below one in 400 individuals [2], the incidence is 2–3 per 100,000 in Europe [3]. Neurodegenerative processes with altered homeostasis, protein accumulation and cell death generates neuroinflammation, and central nervous system (CNS)-resident immune cells such as astrocytes and microglia trigger neuroinflammation and neurodegeneration [7]. Inflammation may arise reactive to ALS-related CNS alterations, and play an initial role and trigger both onset of disease and further accelerate progression of ALS [3]. A complex, cytokinemediated crosstalk between CNS and systemic immune cells regulates immune responses to either pro- or anti-inflammatory states, which evolve over time [7]
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