Amyotrophic Lateral Sclerosis. 2009; 10: 430431
ORIGINAL ARTICLE
Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis
YUANJIN ZHANG, LIPING WANG, YU FU, HONGSONG SONG, HAIYAN ZHAO, MIN DENG, JUN ZHANG & DONGSHENG FAN Amyotroph Lateral Scler Downloaded from informahealthcare.com by 212.115.233.64 on 05/20/14 For personal use only.
Department of Neurology, Peking University Third Hospital, Beijing, China
Abstract We investigated the safety and efficacy of the granulocyte colony stimulating factor (G-CSF) in 13 patients with amyotrophic lateral sclerosis (ALS). Five-day administration of 2 mg/kg once a day was followed by a six-month observation period. The primary and secondary endpoints were the changes of ALS functional rating scale (ALSFRS) and the compound muscle action potential (CMAP) amplitude, respectively. We found that the declines of ALSFRS and CMAP amplitude after G-CSF administration were significantly less than those measured prior to the treatment. The results suggest G-CSF is safe in ALS patients, and may affect the rate of motor decline. Key words: Amyotrophic lateral sclerosis, granulocyte colony stimulating factor, ALS functional rating scale, compound
muscle action potential amplitude
Introduction
Results
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Riluzole is the only approved drug to delay its progression (1). In this study, we sought to investigate the safety and efficacy of granulocyte colony stimulating factor (G-CSF), a novel neurotrophic factor (2) in ALS patients.
Thirteen subjects were enrolled but three were lost at six months after administration because of telephone contact failure. Leucocyte number of all participants increased at five days after administration. CD34 cell percentage was 1.190.7%, indicating effective mobilization of bone marrow cells. The declines of ALSFRS and CMAP amplitude during the first three months after G-CSF treatment were significantly less than those during the three months prior to treatment ( pB0.05). In the second three months after treatment, the change of ALSFRS was significantly greater than in the first three months ( pB0.01). However, no significant change in decline was observed in CMAP amplitude during the second three months of observation ( p0.05) (Table I). Two patients had symptoms of infection in the third day after treatment and three others had mild fever on the second or third day.
Methods Thirteen subjects were enrolled after providing informed consent. All had a diagnosis of definite or probable ALS with duration less than 3.5 years, and forced vital capacity greater than 45%. Participants were observed from three months before administration to six months after administration. Since G-CSF had never been administered for ALS patients, subcutaneous injections were administered within an open trial setting of 2 g/kg once a day for five days in line with a minor level of the approved dose. The primary and secondary endpoints were changes of ALS functional rating scale (ALSFRS) and compound muscle action potential (CMAP) amplitude, respectively.
Discussion G-CSF is a traditional haematopoietic growth factor that was approved by the US Food and Drug
Correspondence: D. Fan, Department of Neurology, Peking University Third Hospital, 49 North Garden Rd, Haidian District Beijing 100191, China. E-mail:
[email protected] (Received 11 June 2008; accepted 28 October 2008) ISSN 1748-2968 print/ISSN 1471-180X online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.3109/17482960802588059
0.3491.50 2.4391.55 3.1591.96 3.7892.70
3.0992.01
26.399.2
CMAP amplitude p-values
ALSFRS p-values
Mean9SD 30 vs. 03 03 vs. 36 Mean9SD 30 vs. 03 03 vs. 36
30.599.0
27.399.5
26.799.2
0.6991.18
0.6291.12 0.012* 0.009* 0.0690.60 0.023* 0.093 3.2392.83
1.6091.07
Change in the first three months after treatment Change in the three months prior to treatment Six months after administration Three months after administration At administration Three months prior to administration
Table I. Effect of G-CSF on changes of ALSFRS and CMAP amplitude.
Amyotroph Lateral Scler Downloaded from informahealthcare.com by 212.115.233.64 on 05/20/14 For personal use only.
Change in the second three months after treatment
G-SCF and ALS
431
Administration for granulocytopenia therapy (3). Recently, Tanaka et al. (4) found that G-CSF had a protective effect on NSC34 cell line, a mouse motor neuron cell line, under conditions of both oxidative and nutritional stress through G-CSF receptor expression in the cells. They found that G-CSF treatment significantly improved cell viability in a dose-dependent manner. G-CSF is also a novel neurotrophic factor with many properties that can contribute to neuronal recovery following injury (2). Subcutaneous G-CSF can cross the blood-brain barrier, and has been shown previously to be relatively safe. In a study of 101 volunteers who were administered G-CSF over a five-year period, no untoward effects were identified (5). Shapira et al. (6) administered G-CSF (10 mg/kg/day for five days) to 18 normal marrow donors, and examined the extent of double-stranded DNA relaxation and instability index. They found the indexes were maximal at the fifth day and decreased to normal at the first or second month, which showed that G-CSF does not induce longterm DNA instability. In the present study, we found that G-CSF treatment was safe in ALS patients. The rate of reduction of ALSFRS and CMAP amplitude was significantly lower after the treatment, which suggested that G-CSF might delay the progression of functional decline in ALS. However, the findings from this open-label trial cannot be considered conclusive, and will require validation by a larger randomized, placebo-controlled, double-blinded study. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis/motor neuron disease. ALS. 2003;4:191206. 2. Solaroglu I, Cahill J, Jadhav V. A novel neuroprotectant G-CSF. Stroke. 2006;37:11238. 3. Hubel K, Engert A. Clinical applications of G-CSF: an update and summary. Ann Hematol. 2003;82:20713. 4. Tanaka M, Kikuchi H, Ishizu T, Minohara M, Osoegawa M, Motomura K, et al. Intrathecal up-regulation of G-CSF and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2006;65:81625. 5. Cavallaro AM, Lilleby K, Majolino I, Storb R, Appelbaum FR, Rowley SD, et al. Three- to six-year follow-up of normal donors who received recombinant human G-CSF. Bone Marrow Transplant. 2000;25:859. 6. Shapira MY, Kaspler P, Samuel S, Shoshan S, Or R. G-CSF does not induce long-term DNA instability in healthy peripheral blood stem cell donors. Am J Hematol. 2003;73:336.
