Therapy Academic Industry Roundtable Research Articles

Bone marrow stromal cell therapy for ischemic stroke: A meta-analysis of randomized control animal trials.

Background Results of animal studies assessing efficacy of bone marrow stromal cell therapy for ischemic stroke remain inconsistent. Aims The aims are to assess efficacy of bone marrow stromal cell therapy for ischemic stroke in animal studies. Methods Randomized controlled animal trials assessing efficacy of bone marrow stromal cell therapy were eligible. Stroke therapy academic industry round table was used to assess methodologic quality of included studies. Primary outcomes were total infarction volume and modified Neurological Severity Score. Multiple prespecified sensitivity analyses and subgroup analyses were conducted. Random effects models were used for meta-analysis. Results Thirty-three randomized animal trials were included with a total of 796 animals. The median quality score was 6 (interquartile range, 5-7). Bone marrow stromal cell therapy decreased total infarction volume (standardized mean difference, 0.897; 95% confidence interval, 0.553-1.241; P < .001) at follow-up. Overall standardized mean difference between animals treated with bone marrow stromal cell and controls was 2.47 (95% confidence interval, 1.84-3.11; P < .001) for modified Neurological Severity Score; 1.27 (95% confidence interval, 0.72-1.82; P < .001) for adhesive removal test; and 2.13 (95% confidence interval, 0.65-3.61; P < .001) for rotarod test. Significant heterogeneity among studies was observed. Effect of all outcomes stayed significant in various sensitivity analyses and subgroup analyses, except in a few subgroup analyses with small sample size or with short time follow-up. No significant difference between groups was observed except for study location, in which significantly larger estimates were found in Asian countries. On the basis of this meta-analysis, larger sample sizes are warranted for future animal studies. Conclusions Bone marrow stromal cell therapy significantly decreased total infarction volume and increased neural functional recovery in randomized controlled animal models of ischemic stroke.

Misleading Results: Translational Challenges

We agree completely with the news focus story “When mice mislead” (J. Couzin-Frankel, 22 November 2013, p. [922][1]). Many of the issues identified in this article, such as investigator bias, blinding, randomization, and inclusion and exclusion criteria, were clearly identified in the Stroke Therapy Academic Industry Round Table publication in 1999 ([ 1 ][2]) and discussed further by others ([ 2 ][3]). Tightening the standards for animal experimentation, especially for those experiments that test drugs for their neuroprotective effects, is critical as we try to translate these drugs into human stroke therapy. There have been hundreds of drugs tested for neuroprotective effects and many, if not most, have positive effects, in animal models. If a mouse or rat had a stroke, we would know exactly how to treat it. Unfortunately, none of these drugs has shown success in humans. It is unlikely that poor methods used in animal studies account for all the negative clinical trials that have been performed based on preclinical studies. After all, some investigators do perform appropriate experiments, and even those studies rarely lead to positive clinical trials. One important issue not mentioned in the News Focus piece could also account for the lack of positive clinical trials: Most researchers in the stroke field work with normal, young, healthy animals. Humans who participate in neuroprotective drug clinical trials are most often not normal, young, or healthy. They have a variety of comorbid diseases such as hypertension, diabetes, obesity, and vascular disease, which could alter the way in which drugs work in humans. We suggest that in future animal experiments, drugs be tested in animals that are aged, with comorbid diseases. Such studies may help to identify potentially effective drugs in an animal model that mimics more closely a human with stroke. 1. [↵][4]Stroke Therapy Academic Industry Round Table, Stroke 30, 2752 (1999). [OpenUrl][5][Abstract/FREE Full Text][6] 2. [↵][7]1. M. M. Macleod 2. et al ., J. Cerebral Blood Flow Met. 29, 221 (2009). [OpenUrl][8][Abstract/FREE Full Text][9] [1]: /lookup/doi/10.1126/science.342.6161.922 [2]: #ref-1 [3]: #ref-2 [4]: #xref-ref-1-1 View reference 1 in text [5]: {openurl}?query=rft.jtitle%253DStroke%26rft.stitle%253DStroke%26rft.volume%253D30%26rft.issue%253D12%26rft.spage%253D2752%26rft.epage%253D2758%26rft.atitle%253DRecommendations%2Bfor%2BStandards%2BRegarding%2BPreclinical%2BNeuroprotective%2Band%2BRestorative%2BDrug%2BDevelopment%26rft_id%253Dinfo%253Adoi%252F10.1161%252F01.STR.30.12.2752%26rft_id%253Dinfo%253Apmid%252F10583007%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToic3Ryb2tlYWhhIjtzOjU6InJlc2lkIjtzOjEwOiIzMC8xMi8yNzUyIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzQzLzYxNjkvMzY5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [7]: #xref-ref-2-1 View reference 2 in text [8]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2BCerebral%2BBlood%2BFlow%2Band%2BMetabolism%26rft.stitle%253DJ%2BCereb%2BBlood%2BFlow%2BMetab%26rft.aulast%253DMacleod%26rft.auinit1%253DM.%2BR.%26rft.volume%253D29%26rft.issue%253D2%26rft.spage%253D221%26rft.epage%253D223%26rft.atitle%253DReprint%253A%2BGood%2BLaboratory%2BPractice%253A%2BPreventing%2BIntroduction%2Bof%2BBias%2Bat%2Bthe%2BBench%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fjcbfm.2008.101%26rft_id%253Dinfo%253Apmid%252F18797473%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [9]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BqY2IiO3M6NToicmVzaWQiO3M6ODoiMjkvMi8yMjEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNDMvNjE2OS8zNjkuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9

Spontaneously hypertensive rats display reduced microglial activation in response to ischemic stroke and lipopolysaccharide

BackgroundFor successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals.MethodsThe vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and Spontaneously Hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the Laser Doppler technique. Infarct size was assessed histologically by Cresyl Violet staining. Sensory-motor functions were measured at several time points using the Neurological Deficit Score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein.Results and conclusionsThe SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.

Protective Effects of Pioglitazone Against Global Cerebral Ischemic-Reperfusion Injury in Gerbils

Despite of the huge socio-economic burden, stroke still represents an unmet therapeutic need. Researchers failed to reproduce preclinical efficacy in subsequent clinical development. To bridge this translation failure, the Stroke Therapy Academic Industry Round Table (STAIR) has suggested a rigorous, robust, and detailed preclinical evaluation in at least 2 species and multiple cerebral ischemia models to avoid the clinical failure. Considering these recommendations, in the present study, we have investigated the effects of pioglitazone in global model cerebral ischemic-reperfusion (IR) injury in gerbils. Global cerebral IR injury, produced by bilateral carotid artery occlusion for 5 min, was characterized by neurological deficits, hyperlocomotion, and neurodegeneration in the hippocampal CA1 region. Global ischemia was also associated with oxidative stress and DNA fragmentation as evident from increased malondialdehyde (MDA) levels and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells. Global cerebral IR injury associated neurological damage was significantly attenuated by pioglitazone pretreatment as evident from reduction in neurological symptoms, hyperlocomotion, and CA1 hippocampal neuronal damage in IR-challenged gerbils. Pioglitazone pretreatment also attenuated the oxidative stress and DNA fragmentation after cerebral IR injury. Pioglitazone post-treatment has also significantly reduced the CA1 hippocampal neuronal damage and DNA fragmentation after cerebral IR injury in IR-challenged gerbils. This study demonstrates the neuroprotective activity of pioglitazone in global cerebral IR injury and its neuroprotective effects may be attributed to reduction in oxidative stress and DNA fragmentation.

Missing Steps in the STAIR Case: A Translational Medicine Perspective on the Development of NXY-059 for Treatment of Acute Ischemic Stroke

The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The disappointment was heightened by the latter study being viewed as a most promising compound for stroke drug development program based on the preclinical data. Since the SAINT I/II development program included many of the STAIR (Stroke Therapy Academic Industry Round table) guidelines, yet have still failed to achieve the expected efficacy, there is a clear need to continue and analyze the path forward for stroke drug discovery. To this end, this review calls for a consortium approach including academia, government (FDA/NIH), and pharmaceutical industry partnerships to define this path. It is also imperative that more attention is given to the evolving discipline of Translational Medicine. A key issue in this respect is the need to devote more attention to the characteristics of the drug candidate nature-target interaction, and its relationship to pharmacodynamic treatment end points. It is equally important that efforts are spent to prove that phenotypic outcomes are linked to the purported mechanism of action of the compound. Development of technologies that allows a better assessment of these parameters, especially in in vivo models are paramount. Finally, rational patient selection and new outcome scales tailored in an adaptive design model must be evaluated.