{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:54:32Z","timestamp":1790823272638,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Op2Lysis SAS"},{"DOI":"10.13039\/501100003032","name":"ANRT","doi-asserted-by":"publisher","award":["CIFRE 2017\/1494"],"award-info":[{"award-number":["CIFRE 2017\/1494"]}],"id":[{"id":"10.13039\/501100003032","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016308","name":"Bpifrance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016308","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012948","name":"Ministry of Higher Education, Research and Innovation","doi-asserted-by":"publisher","award":["i-LAB 2017"],"award-info":[{"award-number":["i-LAB 2017"]}],"id":[{"id":"10.13039\/100012948","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma. Updated guidelines (2022) for the management of intracerebral haemorrhage patients recognize that minimally invasive approaches for the evacuation of supratentorial intracerebral haemorrhage have demonstrated reductions in mortality compared with medical management alone. However, improvement of functional outcome with a procedure involving thrombolytic therapy was neutral in the last large phase 3 clinical trial and requires a more effective and safer thrombolytic agent than those currently available. Here, we demonstrate that O2L-001 allows for the extended release of W253R\/R275S recombinant tissue-type plasminogen activator (rtPA). A new rtPA variant, called optimized tPA (OptPA), offers improved efficacy for haematoma evacuation as well as improved safety.<\/jats:p>\n               <jats:p>OptPA was produced in a Chinese hamster ovary cell line before purification, nanoprecipitation using the NANOp2Lysis\u00ae technological platform followed by suspension in a solution of 17% poloxamer 407 to obtain O2L-001. Plasmin generation assays were performed to demonstrate O2L-001 safety. Ex vivo haematoma models using human blood were used to demonstrate O2L-001 thrombolysis properties and efficacy. For the best translational significance, a clinical sized haematoma was used to ensure catheter placement and to allow administration of the thrombolytic agent into the core of the haematoma via a minimally invasive procedure.<\/jats:p>\n               <jats:p>The capacity of OptPA to convert plasminogen into plasmin is strongly decreased compared to rtPA, thereby reducing potential bleeding events. However, a clot lysis assay showed that OptPA had the same fibrinolytic activity as rtPA. We demonstrated that long-term exposure to a thrombolytic agent was essential to achieve high thrombolysis efficacy. Indeed, 24 h continuous exposure to 0.1 \u00b5g\/ml rtPA had similar efficacy than repeated short exposure to 30 \u00b5g\/ml rtPA.<\/jats:p>\n               <jats:p>This finding led to the development of O2L-001, allowing the extended release of OptPA in the first 6 h following injection. An ex vivo model using human blood was used to demonstrate O2L-001 efficacy. Interestingly, unlike rtPA, O2L-001 was able to induce the complete lysis of the 5 ml haematoma. In clinical sized haematomas (obtained from 30 ml of human blood), a single injection of O2L-001 at 1 mg\/ml into the core of the haematoma led to a 44% increase in thrombolysis compared to rtPA.<\/jats:p>\n               <jats:p>Taken together, these results demonstrate that O2L-001 provides new hope for haematoma evacuation and the treatment of patients with intracerebral haemorrhage.<\/jats:p>","DOI":"10.1093\/brain\/awad237","type":"journal-article","created":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T20:25:47Z","timestamp":1689279947000},"page":"4690-4701","source":"Crossref","is-referenced-by-count":3,"title":["O2L-001, an innovative thrombolytic to evacuate intracerebral haematoma"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-5560","authenticated-orcid":false,"given":"Audrey M","family":"Thiebaut","sequence":"first","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle R","family":"Louet","sequence":"additional","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"},{"name":"Normandie Univ, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C) , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lina","family":"Ianszen","sequence":"additional","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Julie","family":"Guichard","sequence":"additional","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F","family":"Hanley","sequence":"additional","affiliation":[{"name":"The Johns Hopkins Medical Institutions, BIOS , Baltimore, MD 21202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Gaudin","sequence":"additional","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Parcq","sequence":"additional","affiliation":[{"name":"Op2Lysis SAS, GIP Cyceron , 14000 Caen , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"2023110723351765300_awad237-B1","doi-asserted-by":"crossref","first-page":"795\u2013","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the global burden of disease study 2019","volume":"20","author":"Feigin","year":"2021","journal-title":"Lancet Neurol"},{"key":"2023110723351765300_awad237-B2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1177\/2396987319883160","article-title":"Economic burden of stroke across Europe: A population-based cost analysis","volume":"5","author":"Luengo-Fernandez","year":"2020","journal-title":"Eur Stroke J"},{"key":"2023110723351765300_awad237-B3","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/S0140-6736(19)30195-3","article-title":"Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): A randomised, controlled, open-label, blinded endpoint phase 3 trial","volume":"393","author":"Hanley","year":"2019","journal-title":"Lancet"},{"key":"2023110723351765300_awad237-B4","doi-asserted-by":"crossref","first-page":"5472936","DOI":"10.1155\/2017\/5472936","article-title":"Optimization of catheter based rtPA thrombolysis in a novel in vitro clot model for intracerebral hemorrhage","volume":"2017","author":"Keric","year":"2017","journal-title":"Biomed Res Int"},{"key":"2023110723351765300_awad237-B5","doi-asserted-by":"crossref","first-page":"e343","DOI":"10.1161\/STR.0000000000000152","article-title":"Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: A scientific statement for healthcare professionals from the American heart association\/American stroke association","volume":"48","author":"Yaghi","year":"2017","journal-title":"Stroke"},{"key":"2023110723351765300_awad237-B6","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/s00401-017-1749-z","article-title":"Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke","volume":"134","author":"Su","year":"2017","journal-title":"Acta Neuropathol"},{"key":"2023110723351765300_awad237-B7","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1172\/JCI200319212","article-title":"Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein","volume":"112","author":"Yepes","year":"2003","journal-title":"J Clin Invest"},{"key":"2023110723351765300_awad237-B8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.atherosclerosis.2012.10.072","article-title":"Platelet derived growth factor-CC isoform is associated with hemorrhagic transformation in ischemic stroke patients treated with tissue plasminogen activator","volume":"226","author":"Rodr\u00edguez-Gonz\u00e1lez","year":"2013","journal-title":"Atherosclerosis"},{"key":"2023110723351765300_awad237-B9","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1182\/blood-2016-03-705384","article-title":"Hyperfibrinolysis increases blood\u2013brain barrier permeability by a plasmin- and bradykinin-dependent mechanism","volume":"128","author":"Marcos-Contreras","year":"2016","journal-title":"Blood"},{"key":"2023110723351765300_awad237-B10","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/83358","article-title":"The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling","volume":"7","author":"Nicole","year":"2001","journal-title":"Nat Med."},{"key":"2023110723351765300_awad237-B11","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1161\/STROKEAHA.110.606293","article-title":"Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis","volume":"42","author":"MacRez","year":"2011","journal-title":"Stroke"},{"key":"2023110723351765300_awad237-B12","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1177\/0271678X17719180","article-title":"Optimized tPA: A non-neurotoxic fibrinolytic agent for the drainage of intracerebral hemorrhages","volume":"38","author":"Goulay","year":"2018","journal-title":"J Cereb Blood Flow Metab"},{"key":"2023110723351765300_awad237-B13","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/S1474-4422(18)30323-5","article-title":"The role of plasminogen activators in stroke treatment: Fibrinolysis and beyond","volume":"17","author":"Thiebaut","year":"2018","journal-title":"Lancet Neurol"},{"key":"2023110723351765300_awad237-B14","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.apsb.2017.03.003","article-title":"In vivo retention of poloxamer-based in situ hydrogels for vaginal application in mouse and rat models","volume":"7","author":"Liu","year":"2017","journal-title":"Acta Pharm Sin B"},{"key":"2023110723351765300_awad237-B15","first-page":"491","article-title":"In vitro combinations of red blood cell, plasma and platelet components evaluated by thromboelastography","volume":"12","author":"\u00c5gren","year":"2014","journal-title":"Blood Transfus"},{"key":"2023110723351765300_awad237-B16"},{"key":"2023110723351765300_awad237-B17","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1001\/jamaneurol.2013.98","article-title":"Predictors of haematoma volume in deep and lobar supratentorial intracerebral hemorrhage","volume":"70","author":"Falcone","year":"2013","journal-title":"JAMA Neurol"},{"key":"2023110723351765300_awad237-B18","doi-asserted-by":"crossref","first-page":"954","DOI":"10.3171\/jns.2002.97.4.0954","article-title":"Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: Rapid reduction in haematoma volume but intensification of delayed edema formation","volume":"97","author":"Rohde","year":"2002","journal-title":"J Neurosurg"},{"key":"2023110723351765300_awad237-B19","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3171\/jns.2007.106.2.314","article-title":"Addition of intravenous N-methyl-D-aspartate receptor antagonists to local fibrinolytic therapy for the optimal treatment of experimental intracerebral hemorrhages","volume":"106","author":"Thiex","year":"2007","journal-title":"J Neurosurg"},{"key":"2023110723351765300_awad237-B20","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1038\/cdd.2012.86","article-title":"Unveiling an exceptional zymogen: The single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity","volume":"19","author":"Parcq","year":"2012","journal-title":"Cell Death Differ"},{"key":"2023110723351765300_awad237-B21","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1038\/s41598-017-02498-2","article-title":"Development and validation of a high throughput whole blood thrombolysis plate assay","volume":"7","author":"Bonnard","year":"2017","journal-title":"Sci Rep"},{"key":"2023110723351765300_awad237-B22","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1056\/NEJMoa1515510","article-title":"Low-Dose versus standard-dose intravenous alteplase in acute ischemic stroke","volume":"374","author":"Anderson","year":"2016","journal-title":"N Engl J Med."},{"key":"2023110723351765300_awad237-B23","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1093\/neuros\/nyz077","article-title":"Surgical performance determines functional outcome benefit in the minimally invasive surgery plus recombinant tissue plasminogen activator for intracerebral hemorrhage evacuation (MISTIE) procedure","volume":"84","author":"Awad","year":"2019","journal-title":"Neurosurgery"},{"key":"2023110723351765300_awad237-B24","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1161\/STROKEAHA.111.625749","article-title":"Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage the CLEAR IVH study group","volume":"42","author":"Herrick","year":"2011","journal-title":"Stroke"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awad237\/51698646\/awad237.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/11\/4690\/52808938\/awad237.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/11\/4690\/52808938\/awad237.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T23:35:57Z","timestamp":1699400157000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/146\/11\/4690\/7224419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,7,14]]},"published-print":{"date-parts":[[2023,11,2]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awad237","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,11]]},"published":{"date-parts":[[2023,7,14]]}}}