Letter by Taguchi et al Regarding Article, “Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke: Results of the AX200 for Ischemic Stroke Trial”
To the Editor:
We read with interest a recent article by Ringelstein et al.1 The authors described the results of a phase 2B clinical trial of granulocyte colony-stimulating factor (G-CSF) for patients with stroke, which did not result in any beneficial effects. The authors concluded that the failure of this clinical trial was mainly attributable to the problem of translating findings from the animal laboratory to patients with clinical stroke and thus raised the question, “Are rodent models questionable for predicting stroke drug efficacy in humans?” However, we think that the negative results of this clinical trial had been predictable from previous results of basic experiments with animal models.
The clinical trial was designed on the basis of a meta-analysis of experimental models of cerebral ischemia.2 However, in the majority of cases, the experiments that were included were of transient cerebral ischemia ranging from 1 to 3 hours. Transient ischemia is a model of ischemia-reperfusion injury, and the therapeutic target is mainly protection from apoptotic neural cell death caused by oxidative stress after reperfusion. In contrast, most cases of human stroke show massive necrotic neural cell death caused by a poor supply of cerebral blood flow. Although, in the end, neural cell death is observed in both types of ischemia, the actual pathological states and therapeutic targets are different from each other, and the discrepancy between apoptotic and necrotic cell death should be considered when the clinical trial is designed. We point out that we clearly demonstrated that G-CSF has a negative effect on stroke outcome using a permanent cerebral artery ligation model in immunocompetent mice, and we drew attention to the discrepancy between transient and permanent cerebral occlusion models.3 Furthermore, activated granulocyte, which is significantly mobilized by G-CSF from bone marrow to peripheral blood, is well known to enhance brain damage in experimental stroke model through enhancing inflammation at the site of cerebral ischemia.4 Therefore, it is not surprising that the results of the clinical study show that G-CSF has no therapeutic effect on the outcome of patients with stroke, and the results are not dissimilar to previous findings shown in an experimental stroke model.
In conclusion, we think that it is not rational to conclude that rodent models are questionable in predicting stroke drug efficacy in humans. With regard to the clinical trial in question, previous findings obtained by basic experiments had predicted the negative effect of G-CSF on stroke outcomes (ie, other than experiments with transient ischemia models that mimic patients who had reperfusion injury after recanalization; however, this is not the case with majority of patients with stroke). We think that rodent models are useful for human trials as long as the therapeutic target and the patients enrolled are given proper consideration when the clinical trial is first designed.
Akihiko Taguchi, MD
Yukiko Kasahara, PhD
Department of Regenerative Medicine Research
Institute of Biomedical Research and Innovation
Tomohiro Matsuyama, MD
Laboratory of Neurogenesis and CNS Repair
Institute for Advanced Medical Sciences
Hyogo College of Medicine
Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited.
- © 2013 American Heart Association, Inc.
- Ringelstein EB,
- Thijs V,
- Norrving B,
- Chamorro A,
- Aichner F,
- Grond M,
- et al
- Minnerup J,
- Heidrich J,
- Wellmann J,
- Rogalewski A,
- Schneider A,
- Schäbitz WR