Complement in disease: a defence system turning offensive

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Ref: Nat Rev Nephrol. 2016 May 23. doi: 10.1038/nrneph.2016.70. [Epub ahead of print]

Authors: Ricklin D, Reis ES, Lambris JD.

Highlights:

  • Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists.
  • The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases.
  • Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention.
  • This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

Source: www.nature.com

Study on inhibiting pre-exisiting natural periodontitis with Cp40 receives high Altmetric score

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The study titled “Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered inhibitor of Complement C3″ led by Dr. George Hajishengallis and Dr. John Lambris has been recently assigned a high Altmetric score. Specifically, an Altmetric score serves as “an indicator of the amount of attention that a [research output] has received” from news outlets, as well as multiple social media sites. With a score of 190, this study is in the top 5% of all research outputs ever tracked by Altmetric. Additionally, this study is the #1 research output from its source, the Journal of Clinical Periodontology; specifically, it is ranked #1 out of 587 outputs from this particular journal.

To read more on the Altmetric score of this particular study: www.wiley.altmetric.com

To read more on how an Altmetric score is calculated: www.wiley.altmetric.com

Study on reversing periodontitis with Cp40 features on 6 ABC Action News

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The study titled “Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3″ led by Dr. John Lambris and Dr. George Hajishengallis was recently featured on 6 ABC Action News. The study, which was published in the Journal of Clinical Periodontology, has provided new hope for “millions of Americans,” as the video notes, for a treatment that may effectively reverse periodontitis. The study delivered Cp40, an inhibitor of protein C3, to the periodontal tissue just once a week. This reversed naturally occurring chronic periodontitis inflammation in a preclinical model, and “gums were looking much healthier” in the used animal model, the video also states.

To watch news clip: www.youtube.com

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

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Ref: Seminars in Immunology. 2016 Mar 26. doi:10.1016/j.smim.2016.03.006.

Authors: George Hajishengallis, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Baomei Wang, Despina Yancopoulou, Daniel Ricklin, John D. Lambris.

Highlights:

  • Current therapies for periodontitis are not always effective and this prevalent oral disease continues to be a significant health and economic burden.
  • Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss.
  • This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis.
  • In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates.
  • These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.
  • Source: http://linkinghub.elsevier.com

    Press Release: Penn Team Reverses Signs of Naturally Occurring Chronic Periodontitis

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    A study published in the Journal of Clinical Periodontology led by George Hajishengallis and John D. Lambris has provided new hope that periodontitis can be effectively reversed. Highlights from the press release:

    • The study delivered Cp40, an inhibitor of protein C3, to the periodontal tissue just once a week reversed naturally occurring chronic periodontitis inflammation in a preclinical model.
    • This study builds on earlier work by Hajishengallis, Lambris and colleagues which identified C3 as a promising target for treating periodontal disease.
    • Their previous research, which used an inducible model of periodontal disease, found that Cp40 could reduce signs of the disease.
    • The current work was conducted on animals that naturally had developed chronic periodontitis. Initially the research team tried administering Cp40 three times a week, but after seeing significant reductions in inflammation, they tried giving it only once a week to a different group and saw the same good results.
    • The researchers are even more encouraged that this treatment worked well as a stand-alone therapy; in humans, they said, it would be given in addition to the standard of care scaling and planing. They are planning to pursue a Phase 1 safety and efficacy study in human volunteers.

    Source: https://news.upenn.edu

    Press Release: Amyndas’ lead candidate AMY-101 receives orphan drug status from the FDA and the EMA for the treatment of C3 glomerulopathy

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    Amyndas Pharmaceuticals SA recently announced that its lead candidate, the C3 complement inhibitor AMY-101, has been granted orphan designation by the European Medicines Agency (EMA) and the U.S. FDA for the treatment of C3 glomerulopathy (C3G).” Highlights from the press release:

    • AMY-101 is the first drug to be granted an orphan drug status by the EMA and the U.S. FDA for the indication of C3G.
    • In recent studies AMY-101 was shown to inhibit complement dysregulation in C3G in vitro, presenting a promising therapeutic opportunity and potentially a major advancement for patients with C3G.
    • Half of all patients with C3G progress to end-stage renal failure within 10 years of diagnosis; and allograft loss occurs following kidney transplantation secondary to disease relapse in more than 50% of transplant recipients.
    • Currently, there is no treatment for C3G. Management is symptom-based and includes drugs for blood pressure control, such as angiotensin-converting enzyme inhibitors, and immunosuppressive therapy. As the pathology of C3G is due to malfunction of the alternative pathway (AP) of complement, inhibition of complement component C3 is a promising strategy for the development of an effective treatment.

    Source: www.fiercepharma.com

    Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

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    Ref: J Clin Periodontol. 2016 Jan 5. doi: 10.1111/jcpe.12507. [Epub ahead of print]

    Authors: Maekawa T, Briones RA, Resuello RR, Tuplano JV, Hajishengallis E, Kajikawa T, Koutsogiannaki S, Garcia CA, Ricklin D, Lambris JD, Hajishengallis G.

    Highlights:

    • Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period.
    • Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation.
    • Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis. This article is protected by copyright. All rights reserved.

    Source: www.ncbi.nlm.nih.gov

    Commentary: A ‘rule of 3′ to revive Greek science, research and innovation

    Ref: Nat Immunol. 2015 Nov 18;16(12):1206-8. doi: 10.1038/ni.3322.

    Authors: George Kollias and John D. Lambris

    Highlights from commentary: “If research and technology are to become the driving force for turning Greece into a productive society, evidence-based governance, strategic restructuring of infrastructure and a substantial inflow of fresh human capital is urgently needed.”

    “Given the track record of the political leadership in reforming the Greek research and innovation landscape over recent decades, our expectations that the political system by itself can make the difference remain still very low. We are therefore of the opinion that real change will require strong engagement of scientists toward radical reforms. Productive members of the research and innovation community will need to come together and self-organize into an opinion-leading body to provide high-level consultation to policy makers and to push toward reforming current structures, procedures and mentalities. We posit that it is the responsibility of all concerned, whether Greeks in Greece, the numerous Greeks of the diaspora or the many Philhellenes around the world, to passionately act against today’s disappointing national output in the hope that these initiatives will propel Greek research toward substantial scientific, economic and social returns.”

    Source: www.ncbi.nlm.nih.gov

    Applying complement therapeutics to rare diseases

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    Ref: Clinical Immunology.2015 Dec;161(2):225-240. doi:10.1016/j.clim.2015.08.009. [Epub ahead of print].

    Authors: Reis ES, Mastellos DC, Yancopoulou D, Risitano AM, Ricklin D, Lambris JD.

    Highlights:

  • It is estimated that about 350 million people worldwide suffer from rare diseases.
  • The launch of effective treatments for rare diseases is challenging when there is a low disease prevalence and limited scientific insights into the disease mechanisms
  • As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation.
  • Clinical evidence shows the safety and efficacy of complement therapeutics
  • This review provides an overview of the candidates currently in the pharmaceutical pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis.
  • Source: www.ncbi.nlm.nih.gov

    Press Release: The Aplastic Anemia & MDS International Foundation supports Amyndas Pharmaceuticals’ novel complement inhibitor AMY-101

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    Highlights from the press release:

    • Aplastic Anemia & MDS International Foundation (AA&MDSIF) is endorsing the clinical development of Amyndas’ lead candidate AMY-101, as a novel treatment for paroxysmal nocturnal hemoglobinuria (PNH).
    • The AA&MDSIF awarded Prof Risitano (Federico II University in Naples) and Prof Calado (University of Sao Paolo) a grant to fund the first clinical trial of the C3 complement inhibitor AMY-101 in untreated PNH patients. Both are distinguished experts in PNH research.
    • AMY-101 has already undergone extensive pre-clinical development and evaluation, and was found to provide complete and sustained complement inhibition.
    • AMY-101 is  expected to be effective in patients suffering from PNH, even those who do not fully benefit from the current complement-directed standard treatment.

    Source: www.fiercepharma.com