Research Theme: Monomeric-C-reactive protein (mCRP) for Dementia and stroke + [coronary diagnostics and therapeutics]

Project team: Mark Slevin, Donghui Liu, Catherine Fang; Jurek Krupinski; Vittorio DiCaprio. Collaborators: Johannes Boltze (University of X, Germany); Larry Potempa (USA), Coral Sanfeliu (Spain) and UMFST (Romania).

Previous funding: As PI-EU de Cercetare, P_37_674 £2M (2016-2020). In progress, Pre-clinical trial application £500,000; (Fraunhofer, Germany). UEFISCDI-PCE 350K; Patent-held at MMU.

Target funding and collaboration: UEFISCDI/ReNeuron for clinical trials/EU and KTP/Innovate UK

Impact: Our proposed therapeutic with the ability to counteract or block the biological activity of mCRP would be an effective PREVENTITIVE treatment aimed primarily at minimising neurological decline and dementia after brain injury or stroke. In addition, treatment of inflammatory-based autoimmune diseases could benefit from this approach.

Background: One in 3 people will suffer stroke/heart attack by age 65. Approximately 500,000 stroke victims will develop dementia within each year in the UK alone. The cost of treatment of dementia equates to approximately 50K/annum/person, incurring a significant cost to the health service and impacting on families/carers and care home provision. Statistics also show that approximately 50% of people will develop significant neurological decline, limiting their ability to perform basic day-to-day tasks within 1 year of suffering from acute stroke. In addition, all other types of stroke (lacunar, transient, haemorrhagic) are linked to development of dementia and Alzheimer’s disease. The reasons for this are yet to be identified.

C-reactive protein is an acute phase pentraxin produced mainly by the liver during inflammatory processes and is prevalent in the circulation and in brain parenchyma in large quantities after stroke or other brain injury. The monomeric form (mCRP) binds to cells, tissues and blood particulates and is causative of tissue inflammation and within brain tissue, neurodegenerative capacity (published by us in 4* journals-as determined by REF panel rankings allied to SNIP journal metrics; Sci. Rep (1), ATVB, Stroke et al) and seems to be a major causative factor in development of stroke-associated vascular dementia.

Current research programme: Currently, in vivo characterization is being carried out using a murine dementia model, during 2021-2023, both antibodies and specific mCRP blockers produced in-house will be tested for their ability to inhibit neurodegenerative capacity measured by cognition and behavioural testing and later histological and immunohistochemically analysis. Concomitantly in 2021, a proof-of-concept study in sheep took place in UMFST, TM, Romania to investigate the anti-inflammatory properties of mCRP antibodies in stroked-animals and the impact on stroke recovery. We are currently characterising a group of active SMIs- should this work be successful we would anticipate a successful  grant application during 2022 and the possibility of clinical trials around 2023-2024.

Added value: A mechanism to accurately determine a person’s risk of acute myocardial infarction or relapse is urgently needed in the coronary care unites and A&E. We anticipate the missing biomarker is mCRP and are concomitantly developing a high sensitivity ELISA kit to be able to measure this along with a nano-sensing platform that can detect mCRP, Troponin and BNP-the 3 major markers in real-time.

Reference: Monomeric C-reactive protein–a key molecule driving development of Alzheimer’s disease associated with brain ischaemia? Sci Rep. 2015 Sep 3;5:13281. doi: 10.1038/srep13281. Slevin M^1,2,3, Matou S¹, Zeinolabediny Y, Corpas R, Weston R, Liu D, Boras E, Di Napoli M, Petcu E, Sarroca S, Popa-Wagner A, Love S, Font MA, Potempa LA, Al-Baradie R, Sanfeliu C, Revilla S, Badimon L, Krupinski J.