Pilot Study of Granulocyte-Colony Stimulating Factor for Treatment of Alzheimer's Disease

Abstract

Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance.

Visuospatial learning and memory in the Cebus apella and microglial morphology in the molecular layer of the dentate gyrus and CA1 lacunosum molecular layer

“…PAL tasks have been used to investigate the role of the hippocampus in incrementally encoding associations between different stimuli (Blackwell et al, 2004;Skolimowska et al, 2011;Junkkila et al, 2012;Sanchez-Ramos et al, 2012). Our findings provided a basis for new comparisons between New and Old World primates (Taffe et al, 2002;Spinelli et al, 2004) and with human performance (Nagahara et al, 2010).…”

G-CSF as an Adjunctive Therapy with Umbilical Cord Blood Cell Transplantation for Traumatic Brain Injury

“…G-CSF has also been shown to enhance memory and neurobehavioral function in AD animal models (81). Pilot clinical trials reported that administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and it provided positive changes in a hippocampal-dependent task of cognitive performance in AD patients (87).…”

“…Currently, a limited clinical trial is under way for testing G-CSF in TBI patients (personal communication with Dr. Juan SanchezRamos, USF/VA). Despite inconsistent efficacy results, the translation of G-CSF for TBI in the clinic is based on the drug's safety profiles for its indication in acute ischemic stroke and AD (28,87,88,103,104).…”

“…A major component of regenerative medicine is stem cell-based therapeutics, which have shown promising therapeutic potential for various types of neurological disorders, including TBI (e.g., 57,58,62,109,130), and have reached limited clinical trials [for review see (43)]. Translating cell therapy for treatment of brain diseases to the clinic has involved testing the safety, efficacy, and mechanisms of action of a variety of transplantable donor cells, including fetal stem cells, cancer-derived neuron-like cells, embryonic stem cells, induced pluripotent stem cells, and adult stem cells, such as umbilical cord blood, bone marrow stromal cells, amnion cells, among others (16,57,58,62,63,74,75,84,87,90,109,130). However, among these various types of stem cells, adult stem cells are of interest, as they circumvent ethical and moral problems and also teratogenic and oncogenic risks usually associated with transplantation of embryonal or fetal-derived stem cells (85).…”

Alzheimer’s Disease: Dawn of a New Era?

“…They also reported that G-CSF administration induced neurogenesis around Aβ aggregates in these acute and chronic animal models of Aβ-driven AD. In 2012, a pilot clinical study in 8 patients with mild to moderate stages of AD did not show a serious adverse effect for five days of subcutaneous G-CSF administration, but did provide evidence for positive changes in hippocampal-dependent cognitive tasks (190).…”