Katerina Akassoglou

K

Did you enjoy ACTRIMS?

On Thursday evening I had the privilege of being at the Barancik Prize award ceremony and lecture. Katerina Akassoglou received the award for her work on the blood-brain barrier and fibrin as a pro-inflammatory agent of the innate immune system. Her lecture was a tour de force on what a single individual with dedication and focus can achieve. Well done.

I was particularly impressed that Katerina’s group is now translating this work into the clinic and is developing a class of drugs that recognises and blocks a cryptic or hidden binding site on fibrin. Why is this important? When the blood-brain-barrier gets disrupted and fibrinogen, a clotting protein, leaks into the brain and spinal cord and gets is converted into fibrin. As fibrin this cryptic site is exposed, which stimulates a receptor on microglia, called the integrin receptor Mac-1 (also called alpha(M)beta(2) or CD11b/CD18). This receptor activates microglia and causes them to become ‘hot’ like hot chilly peppers. These chilly peppers burn the tissue around them; the activated or hot microglia produce a large number of damaging molecules including reactive oxygen species, which are not good for the brain and spinal cord and cause loss of axons and neurons.

Importantly, the antibody that Katerina has developed blocks the fribrin-microglia interaction has the potential to treat many diseases inclusing Alzheimer’s disease.

The problem I see with this treatment strategy going forward is how to test in MS. Does it get compared to placebo? Does it get added on to existing DMTs? How do you design proof of biology trials? How do you design dose-finding phase 2 trials? And finally, how do you design a phase 3 trial? Do you need to use this treatment continuously or only during the early stages of inflammation? Is it a treatment that is best targeted to progressive MS?

I suspect more CSF biomarker work looking at activated microglia and macrophages, BBB leakage and fibrin formation needs to be done to provide the tools to test this drug in MS.

Despite these challenges, the award will raise awareness of this pathway and the science underpinning it. I suspect big pharma is already all over this pathway and we may see CNS penetrant small molecule inhibitors emerging. If this work translates into clinical practice there will be many more accolades and awards for Katerina.

Well done and thank you for a very inspirational lecture.

Akassoglou et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol. 2018 Nov;19(11):1212-1223.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Akassoglou et al. The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007 Mar 19;204(3):571-82.

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.

About the author

Gavin

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

10 comments

  • I wonder if this is why I have MS- had a dog bite me in the face and ended up going numb a few weeks later with TM and CIS dx which later became MS. The bite was on my lip and I had to remove small pads of gauze a few times a day which ripped off the scab and caused new bleeding. This went on for a while. Could all that clotting have unleashed the fibrinogen?

  • Has anyone recently looked at the work on the Blood Brain Barrier done at Oxford by Professor W. Ritchie Russell around 50 years ago. His booklet “Multiple Sclerosis Control of the Disease” is long since out of print and is no doubt simplistic and anecdotal and indeed “unscientific” by todays standards. But still it might be worth revisiting.

  • Thanks for the post.

    With this groundbreaking breakthrough, where does this leave or how do B and T-cells fit in to it other than a downstream effect? Has this group somehow tied fibrin conversion from fibrinogen through a disrupted BBB to EBV or EBV driven memory B-cells?

    It has become quite apparent that these hot microglia are the ring leader and B and T-cells are an after result. The hot microglia, triggered by these fibrin deposits, appear to be responsible for for the relapses and the progression of MS or the “shredder effect” and the field effect post Tysbari or Gilenya as well.

    • My question is would EBV, directly or indirectly, disrupt the BBB and then fibrinogen cross and forms fibrin, which turns microglia to “hot” and then calls in the cavalry B and T-cells? Has EBV, either directly or indirectly, ever been shown to disrupt the BBB?

      • We know that EBV can trigger pro-inflammatory responses. We have some interesting preliminary data that describe factors that seem to promote neuroinvasion of EBV-positive B cells. We just submitted a grant to study this further, but it will likely not get funded. On the positive side, our paper describing inhibitors of latent EBV is coming out this week in Science Translational Medicine.

  • It seems fundamental on our understanding about the disease. Hot microglia is the target PMS needs. Your theory about relapses being a reaction to something happening in the brain seems correct.
    Where does this leave our theories about existing DMTs?

  • What I don’t understrand: how does that 5B8 antibody cross the blood brain barrier to inhibit fibrin-induced inflammation inside the brain???
    Other mabs (Ocrelizumab, Natalizumab, etc.) don’t cross the bbb…

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