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

Science Translational Medicine

Volumn 7, Issue 299, 2015, Pages

  Llovera, Gemma ^a,b   Hofmann, Kerstin ^a,b   Roth, Stefan ^a,b   Salas Pérdomo, Angelica ^c,d   Ferrer Ferrer, Maura ^c,d   Perego, Carlo ^e   Zanier, Elisa R ^e   Mamrak, Uta ^a,b   Rex, Andre ^f   Party, Hélène ^g   Agin, Véronique ^g   Fauchon, Claudine ^g   Orset, Cyrille ^g   Haelewyn, Benoît ^g   De Simoni, Maria Grazia ^e   Dirnagl, Ulrich ^f   Grittner, Ulrike ^f   Planas, Anna M ^c,d   Plesnila, Nikolaus ^a,b   Vivien, Denis ^g   Liesz, Arthur ^a,b   more..

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b Germany 3 Munich Cluster for Systems Neurology   (Germany)

^c INST D INVESTIGACIONS B   (Spain)

^d INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

^e MARIO NEGRI INSTITUTE FOR PHARMACOLOGICAL RESEARCH   (Italy)

^f CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^g UNIVERSITÉ DE CAEN   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA4 INTEGRIN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY CD49D; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BRAIN INFARCTION; BRAIN INFARCTION SIZE; BRAIN ISCHEMIA; BRAIN REGION; CELL INVASION; CONTROLLED STUDY; DISEASE SEVERITY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG RESEARCH; DRUG RESPONSE; DRUG TARGETING; FEASIBILITY STUDY; LEUKOCYTE MIGRATION; MALE; MIDDLE CEREBRAL ARTERY OCCLUSION; MOUSE; MOUSE MODEL; MULTICENTER STUDY; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROGNOSIS; RANDOMIZED CONTROLLED TRIAL; ACUTE DISEASE; ANIMAL; CLINICAL TRIAL; DISEASE MODEL; HUMAN; IMMUNOLOGY; PRECLINICAL STUDY; RANDOMIZATION; TREATMENT OUTCOME;

ACUTE DISEASE; ANIMALS; ANTIBODIES, MONOCLONAL; BRAIN ISCHEMIA; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; HUMANS; INTEGRIN ALPHA4; MICE; RANDOM ALLOCATION; TREATMENT OUTCOME;

EID: 84938704875     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aaa9853     Document Type: Article

References (56)

1. G. A. Donnan, M. Fisher, M. Macleod, S. M. Davis, Stroke. Lancet 371, 1612-1623 (2008).
2. ?. Chamorro, A. Meisel, A. M. Planas, X. Urra, D. van de Beek, R. Veltkamp, The immunology of acute stroke. Nat. Rev. Neurol. 8, 401-410 (2012).
3. W. Hacke, M. Kaste, E. Bluhmki, M. Brozman, A. D?valos, D. Guidetti, V. Larrue, K. R. Lees, Z. Medeghri, T. Machnig, D. Schneider, R. von Kummer, N. Wahlgren, D. Toni; ECASS Investigators, Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 359, 1317-1329 (2008).
4. E. C. Jauch, J. L. Saver, H. P. Adams Jr., A. Bruno, J. J. Connors, B. M. Demaerschalk, P. Khatri, P. W. McMullan Jr., A. I. Qureshi, K. Rosenfield, P. A. Scott, D. R. Summers, D. Z. Wang, M. Wintermark, H. Yonas; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease, Council on Clinical Cardiology, Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44, 870-947 (2013).
5. V. E. O?Collins, M. R. Macleod, G. A. Donnan, L. L. Horky, B. H. van der Worp, D. W. Howells, 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467-477 (2006).
6. C. Iadecola, J. Anrather, Stroke research at a crossroad: Asking the brain for directions. Nat. Neurosci. 14, 1363-1368 (2011).
7. M. A. Moskowitz, Brain protection: Maybe yes, maybe no. Stroke 41, S85-S86 (2010).
8. J. A. Zivin, M. Fisher, U. DeGirolami, C. C. Hemenway, J. A. Stashak, Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 230, 1289-1292 (1985).
9. K. A. Hossmann, The two pathophysiologies of focal brain ischemia: Implications for translational stroke research. J. Cereb. Blood Flow Metab. 32, 1310-1316 (2012).
10. M. McNutt, Journals unite for reproducibility. Science 346, 679 (2014).
11. C. Kilkenny, W. J. Browne, I. C. Cuthill, M. Emerson, D. G. Altman, Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLOS Biol. 8, e1000412 (2010).
12. D. J. Lefer, R. Bolli, Development of an NIH consortium for preclinicAl AssESsment of CARdioprotective therapies (CAESAR): A paradigm shift in studies of infarct size limitation. J. Cardiovasc. Pharmacol. Ther. 16, 332-339 (2011).
13. U. Dirnagl, A. Hakim, M. Macleod, M. Fisher, D. Howells, S. M. Alan, G. Steinberg, A. Planas, J. Boltze, S. Savitz, C. Iadecola, S. Meairs, A concerted appeal for international cooperation in preclinical stroke research. Stroke 44, 1754-1760 (2013).
14. P. M. Bath, M. R. Macleod, A. R. Green, Emulating multicentre clinical stroke trials: A new paradigm for studying novel interventions in experimental models of stroke. Int. J. Stroke 4, 471-479 (2009).
15. J. Kimmelman, J. S. Mogil, U. Dirnagl, Distinguishing between exploratory and confirmatory preclinical research will improve translation. PLOS Biol. 12, e1001863 (2014).
16. Q. Wang, X. N. Tang, M. A. Yenari, The inflammatory response in stroke. J. Neuroimmunol. 184, 53-68 (2006).
17. B. Engelhardt, L. Sorokin, The blood-brain and the blood-cerebrospinal fluid barriers: Function and dysfunction. Semin. Immunopathol. 31, 497-511 (2009).
18. B. Engelhardt, R. M. Ransohoff, The ins and outs of T-lymphocyte trafficking to the CNS: Anatomical sites and molecular mechanisms. Trends Immunol. 26, 485-495 (2005).
19. R. Rudick, C. Polman, D. Clifford, D. Miller, L. Steinman, Natalizumab: Bench to bedside and beyond. JAMA Neurol. 70, 172-182 (2013).
20. A. Liesz, W. Zhou, ?. Mracsk?, S. Karcher, H. Bauer, S. Schwarting, L. Sun, D. Bruder, S. Stegemann, A. Cerwenka, C. Sommer, A. H. Dalpke, R. Veltkamp, Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 134, 704-720 (2011).
21. K. Becker, D. Kindrick, J. Relton, J. Harlan, R. Winn, Antibody to the a4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 32, 206-211 (2001).
22. J. K. Relton, K. E. Sloan, E. M. Frew, E. T. Whalley, S. P. Adams, R. R. Lobb, Inhibition of a4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke 32, 199-205 (2001).
23. J. Neumann, M. Riek-Burchardt, J. Herz, T. R. Doeppner, R. König, H. Hütten, E. Etemire, L. M?nn, A. Klingberg, T. Fischer, M. W. Görtler, H. J. Heinze, P. Reichardt, B. Schraven, D. M. Hermann, K. G. Reymann, M. Gunzer, Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke. Acta Neuropathol. 129, 259-277 (2015).
24. F. Langhauser, P. Kraft, E. Göb, J. Leinweber, M. K. Schuhmann, K. Lorenz, M. Gelderblom, S. Bittner, S. G. Meuth, H. Wiendl, T. Magnus, C. Kleinschnitz, Blocking of a4 integrin does not protect from acute ischemic stroke in mice. Stroke 45, 1799-1806 (2014).
25. S. T. Carmichael, Rodent models of focal stroke: Size, mechanism, and purpose. NeuroRx 2, 396-409 (2005).
26. W. Zhou, A. Liesz, H. Bauer, C. Sommer, B. Lahrmann, N. Valous, N. Grabe, R. Veltkamp, Postischemic brain infiltration of leukocyte subpopulations differs among murine permanent and transient focal cerebral ischemia models. Brain Pathol. 23, 34-44 (2013).
27. F. Prinz, T. Schlange, K. Asadullah, Believe it or not: How much can we rely on published data on potential drug targets? Nat. Rev. Drug Discov. 10, 712 (2011).
28. C. G. Begley, L. M. Ellis, Drug development: Raise standards for preclinical cancer research. Nature 483, 531-533 (2012).
29. S. Perrin, Preclinical research: Make mouse studies work. Nature 507, 423-425 (2014).
30. G. N. Duda, D. W. Grainger, M. L. Frisk, L. Bruckner-Tuderman, A. Carr, U. Dirnagl, K. M. Einh?upl, S. Gottschalk, E. Gruskin, C. Huber, C. H. June, D. J. Mooney, E. T. Rietschel, G. Schütte, W. Seeger, M. M. Stevens, R. Urban, A. Veldman, G. Wess, H. D. Volk, Changing the mindset in life sciences toward translation: A consensus. Sci. Transl. Med. 6, 264cm12 (2014).
31. M. Endres, B. Engelhardt, J. Koistinaho, O. Lindvall, S. Meairs, J. P. Mohr, A. Planas, N. Rothwell, M. Schwaninger, M. E. Schwab, D. Vivien, T. Wieloch, U. Dirnagl, Improving outcome after stroke: Overcoming the translational roadblock. Cerebrovasc. Dis. 25, 268-278 (2008).
32. S. R. Bornstein, J. Licinio, Improving the efficacy of translational medicine by optimally integrating health care, academia and industry. Nat. Med. 17, 1567-1569 (2011).
33. U. Dirnagl, M. Fisher, International, multicenter randomized preclinical trials in translational stroke research: It?s time to act. J. Cereb. Blood Flow Metab. 32, 933-935 (2012).
34. J. P. Ioannidis, S. Greenland, M. A. Hlatky, M. J. Khoury, M. R. Macleod, D. Moher, K. F. Schulz, R. Tibshirani, Increasing value and reducing waste in research design, conduct, and analysis. Lancet 383, 166-175 (2014).
35. J. P. Ioannidis, Why most published research findings are false. PLOS Med. 2, e124 (2005).
36. N. A. Crossley, E. Sena, J. Goehler, J. Horn, B. van der Worp, P. M. Bath, M. Macleod, U. Dirnagl, Empirical evidence of bias in the design of experimental stroke studies: A metaepidemiologic approach. Stroke 39, 929-934 (2008).
37. D. W. Howells, E. S. Sena, M. R. Macleod, Bringing rigour to translational medicine. Nat. Rev. Neurol. 10, 37-43 (2014).
38. U. Dirnagl, Bench to bedside: The quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab. 26, 1465-1478 (2006).
39. CAMARADES (2014).
40. K. K. Tsilidis, O. A. Panagiotou, E. S. Sena, E. Aretouli, E. Evangelou, D. W. Howells, R. Al-Shahi Salman, M. R. Macleod, J. P. Ioannidis, Evaluation of excess significance bias in animal studies of neurological diseases. PLOS Biol. 11, e1001609 (2013).
41. K. S. Button, J. P. Ioannidis, C. Mokrysz, B. A. Nosek, J. Flint, E. S. Robinson, M. R. Munaf?, Power failure: Why small sample size undermines the reliability of neuroscience. Nat. Rev. Neurosci. 14, 365-376 (2013).
42. Enlimomab Acute Stroke Trial Investigators, Use of anti-ICAM-1 therapy in ischemic stroke: Results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428-1434 (2001).
43. C. Kleinschnitz, N. Schwab, P. Kraft, I. Hagedorn, A. Dreykluft, T. Schwarz, M. Austinat, B. Nieswandt, H. Wiendl, G. Stoll, Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115, 3835-3842 (2010).
44. T. Shichita, Y. Sugiyama, H. Ooboshi, H. Sugimori, R. Nakagawa, I. Takada, T. Iwaki, Y. Okada, M. Iida, D. J. Cua, Y. Iwakura, A. Yoshimura, Pivotal role of cerebral interleukin-17-producing gdT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946-950 (2009).
45. A. E. Baird, The forgotten lymphocyte: Immunity and stroke. Circulation 113, 2035-2036 (2006).
46. G. Yilmaz, T. V. Arumugam, K. Y. Stokes, D. N. Granger, Role of T lymphocytes and interferon-g in ischemic stroke. Circulation 113, 2105-2112 (2006).
47. J. Seok, H. S. Warren, A. G. Cuenca, M. N. Mindrinos, H. V. Baker, W. Xu, D. R. Richards, G. P. McDonald-Smith, H. Gao, L. Hennessy, C. C. Finnerty, C. M. L?pez, S. Honari, E. E. Moore, J. P. Minei, J. Cuschieri, P. E. Bankey, J. L. Johnson, J. Sperry, A. B. Nathens, T. R. Billiar, M. A. West, M. G. Jeschke, M. B. Klein, R. L. Gamelli, N. S. Gibran, B. H. Brownstein, C. Miller-Graziano, S. E. Calvano, P. H. Mason, J. P. Cobb, L. G. Rahme, S. F. Lowry, R. V. Maier, L. L.Moldawer, D. N. Herndon, R. W. Davis, W. Xiao, R. G. Tompkins; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program, Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. U.S.A. 110, 3507-3512 (2013).
48. J. Mestas, C. C. Hughes, Of mice and not men: Differences between mouse and human immunology. J. Immunol. 172, 2731-2738 (2004).
49. W. R. Schabitz, U. Dirnagl, Are we ready to translate T-cell transmigration in stroke? Stroke 45, 1610-1611 (2014).
50. H. X. Chu, H. A. Kim, S. Lee, J. P. Moore, C. T. Chan, A. Vinh, M. Gelderblom, T. V. Arumugam, B. R. Broughton, G. R. Drummond, C. G. Sobey, Immune cell infiltration in malignant middle cerebral artery infarction: Comparison with transient cerebral ischemia. J. Cereb. Blood Flow Metab. 34, 450-459 (2014).
51. M. Balkaya, J. M. Kröber, A. Rex, M. Endres, Assessing post-stroke behavior in mouse models of focal ischemia. J. Cereb. Blood Flow Metab. 33, 330-338 (2013).
52. D. W. Howells, E. S. Sena, V. O?Collins, M. R. Macleod, Improving the efficiency of the development of drugs for stroke. Int. J. Stroke 7, 371-377 (2012).
53. G. Llovera, S. Roth, N. Plesnila, R. Veltkamp, A. Liesz, Modeling stroke in mice: Permanent coagulation of the distal middle cerebral artery. J. Vis. Exp. e51729 (2014).
54. B. J. Jones, D. J. Roberts, The quantitative measurement of motor inco-ordination in naive mice using an accelerating rotarod. J. Pharm. Pharmacol. 20, 302-304 (1968).
55. V. Bouet, M. Boulouard, J. Toutain, D. Divoux, M. Bernaudin, P. Schumann-Bard, T. Freret, The adhesive removal test: A sensitive method to assess sensorimotor deficits in mice. Nat. Protoc. 4, 1560-1564 (2009).
56. F. Orsini, P. Villa, S. Parrella, R. Zangari, E. R. Zanier, R. Gesuete, M. Stravalaci, S. Fumagalli, R. Ottria, J. J. Reina, A. Paladini, E. Micotti, R. Ribeiro-Viana, J. Rojo, V. I. Pavlov, G. L. Stahl, A. Bernardi, M. Gobbi, M. G. De Simoni, Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. Circulation 126, 1484-1494 (2012).