Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia

Llovera, Gemma; Hofmann, Kerstin; Roth, Stefan; Salas-Perdomo, Angélica; Ferrer-Ferrer, Maura; Perego, Carlo; Zanier, Elisa R.; Mamrak, Uta; Rex, André; Party, Hélène; Agin, Véronique; Fauchon, Claudine; Orset, Cyrille; Haelewyn, Benoît; Simoni, Maria Grazia De; Dirnagl, Ulrich; Grittner, Ulrike; Planas, Anna M.; Plesnila, Nikolaus; Vivien, Denis; Liesz, Arthur

doi:10.1126/scitranslmed.aaa9853

Cited by 224 publications

(218 citation statements)

References 57 publications

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“…Previous trials of immunomodulatory therapies have focused on attenuating the detrimental effects of certain immune cells and inflammatory mediators on the extent of tissue damage in the acute phase. Despite solid evidence, including metaanalyses [44], and preclinical randomized trials for the effectiveness of this neuroprotective approach in experimental studies, the translational validity of neuroprotection by immune modulation is presently uncertain [70]. Findings in proof-of-concept neuroimaging studies in T lymphocytes are controversial and require further investigation.…”

Section: Future Directionsmentioning

confidence: 99%

Clinical Trials of Immunomodulation in Ischemic Stroke

2016

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Inflammatory mechanisms are currently considered as a prime target for stroke therapy. There is evidence from animal studies that immune signals and mediators can have both detrimental and beneficial effects in particular stages of the disease process. Moreover, several of these mechanisms are turned on with sufficient delay after ischemia onset to make them amenable to therapeutic intervention. Several clinical proof-of concept trials have investigated the efficacy of different immunomodulatory approaches in patients with stroke. Trials targeting the innate immune system have focused on reduction of microglial activation, inhibition of neutrophil migration, and interleukin-1 receptor blockade, suggesting that interleukin-1 receptor blockade may be a promising strategy. Studies aiming at halting T-cell migration have also been undertaken with controversial findings regarding prevention of infarct growth in neuroimaging studies. Consistently, recent proof-of-concept trials targeting lymphocytes with drugs such as natalizumab and fingolimod have yielded some promising results on clinical endpoints, but confirmation in larger trials is needed. At present, the understanding of the role of immune mechanisms in neurorepair and neurodegeneration is limited. Improving long-term brain function by mitigating prolonged neuroinflammation that was triggered by acute brain injury could be a strategy in addition to neuroprotection.

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Section: Future Directionsmentioning

confidence: 99%

Clinical Trials of Immunomodulation in Ischemic Stroke

2016

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“…For instance, fingolimod, a drug that induces lymphopenia and prevents lymphocyte access to the brain, has shown beneficial effects in stroke animal models [145] and in small clinical trials in ischemic patients with stroke [146,147]. Also, natalizumab, a drug that inhibits leukocyte infiltration, seems to exert some benefits in human stroke (ACTION trial), and a corresponding mouse anti-CD49d antibody has shown protective effects but only in 1 of 2 experimental models of brain ischemia [148]. Larger studies in patients with stroke are needed to demonstrate efficacy and safety of immunodulatory strategies.…”

Section: Sai and Brain Damagementioning

confidence: 99%

Antigen Presentation After Stroke

et al. 2016

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“…Therapeutic hypothermia Reduce oxygen demand, disruption of the blood-brain barrier, free radical formation, excitotoxicity, and inflammation Intravascular cooling (ICTuS2 trial) [38] or surface cooling [47] in IVT-treated patients was safe despite the adverse events (e.g., pneumonia), but did not improve outcome. A multicenter phase III RCT (EuroHYP-1, NCT01833312) is ongoing to evaluate the effect of surface/endovascular cooling after IVT or EVT.…”

Section: Magnesiummentioning

confidence: 99%

Neuroprotective strategies for acute ischemic stroke: recent progress and future perspectives

Bang

2017

Precis Future Med

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Stroke is one of the leading causes of death and most common cause of disability in adult. Despite of recent advances in the recanalization therapy for acute ischemic stroke, the need for neuroprotectants is substantial, to extend the window for recanalization therapy and to prevent neuronal death by ischemic brain injury or by reperfusion injury after successful therapy. Herein, the possible reasons for the failure of neuroprotectants trials during the past two decades and current status of neuroprotective strategies for acute ischemic stroke are discussed. This review will also address the recent advances and future perspectives in preclinical and clinical trials of neuroprotective agents, including the efforts of high quality of transition of preclinical results to clinical trial, genetic studies to trigger neuroprotectants development, application of neuroprotectants at optimal time and duration after stroke, adjuvant approaches, and biomarker-based triage.

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Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia

Abstract: A multicenter preclinical, randomized, controlled trial (pRCT) of a potential stroke treatment in mice demonstrates the feasibility of performing clinical trial–like investigations in animal models.

Cited by 224 publications

References 57 publications

Clinical Trials of Immunomodulation in Ischemic Stroke

Clinical Trials of Immunomodulation in Ischemic Stroke

Antigen Presentation After Stroke

Neuroprotective strategies for acute ischemic stroke: recent progress and future perspectives

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