First-in-class neuroprotective therapy in acute ischemic stroke, poststroke cognitive impairment and mechanistically related diseases by network pharmacology of common signalling targets

• Applicant: Dr. Ana I. Casas Guijarro
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Pharmacology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449729893

• Final Report Year: 2022

Final Report Abstract

Translational stroke research has yielded only one thrombolytic and no neuroprotective therapy over the last decades. Indeed, there is no specific therapy for approximately 45% of patients who suffer from post-stroke disabilities. Interestingly, only single-drug targets were hitherto pursued, whilst we now know that complex diseases are precisely defined by multitarget modules. In addition, preclinical stroke models frequently ignore real-world clinical comorbidities. Here, I propose an in silico-based multitarget approach based on human disease genes linked to ischaemic stroke to identify potential targets subsequently validated in a preclinical model. Specifically, I followed a network pharmacology therapeutic approach where several components of a disease module were simultaneously targeted, combining mechanistically related and thus synergistic drugs. Moreover, to maximally speed-up market entry, we followed a drug repurposing strategy which ensures therapeutic safety and quick access to the pharmaceutic market. This program resulted in a triple network pharmacology therapy (Objective 1) currently been translated to the clinics (Phase II trial), later extended to a long-term ischaemic therapeutic approach (Objective 2). Additionally, we identified a potential stroke biomarker, determining the best therapeutic frame for acute therapy (Objective 4). Finally, I am currently working on extending our findings to a vascular dementia animal model for later validation of a mechanism-based network pharmacology therapy (Objective 3).

Publications

• Network medicine for disease module identification and drug repurposing with the NeDRex platform. Nature Communications, 12(1).
  Sadegh, Sepideh; Skelton, James; Anastasi, Elisa; Bernett, Judith; Blumenthal, David B.; Galindez, Gihanna; Salgado-Albarrán, Marisol; Lazareva, Olga; Flanagan, Keith; Cockell, Simon; Nogales, Cristian; Casas, Ana I.; Schmidt, Harald H. H. W.; Baumbach, Jan; Wipat, Anil & Kacprowski, Tim
  
• Implication of type 4 NADPH oxidase (NOX4) in tauopathy. Redox Biology, 49, 102210.
  Luengo, Enrique; Trigo-Alonso, Paula; Fernández-Mendívil, Cristina; Nuñez, Ángel; del Campo, Marta; Porrero, César; García-Magro, Nuria; Negredo, Pilar; Senar, Sergio; Sánchez-Ramos, Cristina; Bernal, Juan A.; Rábano, Alberto; Hoozemans, Jeroen; Casas, Ana I.; Schmidt, Harald H.H.W. & López, Manuela G.
  
• Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends in Pharmacological Sciences, 43(2), 136-150.
  Nogales, Cristian; Mamdouh, Zeinab M.; List, Markus; Kiel, Christina; Casas, Ana I. & Schmidt, Harald H.H.W.
  
• Platelet depletion does not alter long-term functional outcome after cerebral ischaemia in mice. Brain, Behavior, & Immunity - Health, 24, 100493.
  Steubing, Rebecca D.; Szepanowski, Fabian; David, Christina; Mohamud, Yusuf Ayan; Mencl, Stine; Mausberg, Anne-Kathrin; Langer, Harald F.; Sauter, Manuela; Deuschl, Cornelius; Forsting, Michael; Fender, Anke C.; Hermann, Dirk M.; Casas, Ana I.; Langhauser, Friederike & Kleinschnitz, Christoph
  
• Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives. Stroke, 53(5), 1487-1499.
  De Meyer Simon, F.; Langhauser, Friederike; Haupeltshofer, Steffen; Kleinschnitz, Christoph & Casas, Ana I.
  
• Time‐dependent dual effect of NLRP3 inflammasome in brain ischaemia. British Journal of Pharmacology, 179(7), 1395-1410.
  Palomino‐Antolin, Alejandra; Narros‐Fernández, Paloma; Farré‐Alins, Víctor; Sevilla‐Montero, Javier; Decouty‐Pérez, Celine; Lopez‐Rodriguez, Ana Belen; Fernández, Nuria; Monge, Luis; Casas, Ana I.; Calzada, María José & Egea, Javier
  
• Un-biased housekeeping gene panel selection for high-validity gene expression analysis. Scientific Reports, 12(1).
  Casas, Ana I.; Hassan, Ahmed A.; Manz, Quirin; Wiwie, Christian; Kleikers, Pamela; Egea, Javier; López, Manuela G.; List, Markus; Baumbach, Jan & Schmidt, Harald H. H. W.