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Cleara Biotech

Senescent cells that accumulate in our bodies are a major cause of health problems and enable cancer development as we age. Researchers at Cleara discovered the mechanism how senescent cells escape the natural elimination process. Based on this discovery, Cleara is developing therapeutics to treat patients with a range of diseases caused by this failure to clear senescent cells.

Discovery timeline

  • The early years »

    • DAF16 homologues FOXO3 and 4 regulated by PI3K/PKB/AKT (Kops Nature. 1999 Apr 15;398(6728):630-4. Brunet Cell. 1999 Mar 19;96(6):857-68.)
    • FOXOs involved in cell cycle regulation (Medema Nature. 2000 Apr 13;404(6779):782-7.)
    • FOXOs involved in combatting cellular stress (Kops Nature. 2002 Sep 19;419(6904):316-21.)
    • FOXOs regulated by cellular stress (Essers EMBO J. 2004 Dec 8;23(24):4802-12.
    • FOXOs regulated by cellular stress (Essers Science. 2005 May 20;308(5725):1181-4.)
  • FOXO4 induces senescence in stressed cancer cells

    FOXO4 can physically interact with p53 under conditions of stress. In response to excessive stress signaling, pathways are turned on to counter the negative consequences. FOXO4-p53 signaling is important for this reponse.

  • FOXO4 inhibition induces apoptosis in senescent cells via p53

    FOXO proteins are downstream targets of the senescence response. Oncogene-mutation, as well as other forms of persistent stress can lead to a chronic damage response. As a consequence, anti-stress signaling is activated. This is for instance evident from FOXO4 phosphorylation and activation. This lead us to the following model (e.g. P.L.J. de Keizer, Ph.D. dissertation and de Keizer et al., 2010, Cancer Research):

     

  • First generation of FOXO4-p53 blocking peptides

    Identification by our team that FOXO4 is a pivot in maintaining the viability of senescent cells. Using primary senescent cells, we observed that removing FOXO4 could trigger a “clean” cell death response, known as apoptosis. This created a new window of opportunity to eliminate these deleterious cells. As we found FOXO4 to also exert a protective response to chemotherapy, it additionally opened the door towards development of methods to overcome therapy resistance of cancer cells.

  • Second generation peptide shows efficacy against senescent cells

    Generation of the first and second generation of compounds to eliminate senescent and therapy-resistant cancer cells (e.g. patent US20130288981 A1; 2012). Here, we showed for the first time that not only inhibition of FOXO4 itself, but more specifically, blocking the FOXO4-p53 binding by cell-penetrating peptides could effectively eliminate senescent cells and therapy-resistant cancer cells.

  • Tumors are also sensitive to FOXO4 inhibition

    Development of the third generation of FOXO4-based anti-senescence drugs: the FOXO4-DRI peptide, aka Proxofim. This proved to be effective in counteracting signs of chemotoxicity and, excitingly, was able to restore healthspan in models for fast and natural aging, e.g. fur density, behavior and renal function. (Baar et al., Cell, 2017). This research received worldwide media attention, including coverage in numerous TV and radio shows, newspapers and blogs.

  • Present » Next generation of FOXO4-p53 blocking therapeutics with higher specificity and low off-target toxicity

    Founding of Cleara to continue our evolution of FOXO4-based anti-senescence drugs and generate the fourth generation capable of human translation. Since the selectivity of the third generation compound, FOXO4-DRI, for senescent cells is ~10-fold, it is unfortunately still too dangerous to allow for clinical trials. At Cleara Biotech, it is our mission to improve the safety profile and potency of Proxofim and to do so, we launched the iPROX program to generate “Improved Proxofim”. We are passionate in translating iPROX to humans and combat senescence-driven age-related diseases, including therapy resistant cancer.

Investigation of biomarkers

Every cell in our body has the potential to become senescent as a consequence of various stresses. By unraveling the enormous heterogeneity of senescent cells, our researchers at Cleara identified the genes at the core of the senescence program. In addition, we obtained evidence for the existence of senescence “subtypes” which play different roles in disease development. Based on these discoveries, Cleara is developing new senescence biomarkers for diagnostics and drug targeting.

2012 Identification of a novel biomarker for senescent cells — the nuclear loss of LaminB1 (Freund et al, 2012, JBC)
2013 Generation and characterization of a transgenic mouse model to report senescence and to study the effect of senescence clearance ( US Patent App. 15/067,543,  US Patent 9,901,080,  US Patent App. 14/365,040)
2014 Discovery of a new type of p16+ senescent cells associated to cutaneous wound healing which are associated to a very unique secretory phenotype (Demaria et al, 2014, Dev Cell)
2016 Demonstration that removing senescent cells ameliorate healthspan and reduce tumor progression after treatment with genotoxic therapies (Demaria et al, 2017, Can Discovery)
2017 Comprehensive study on the transcriptional heterogeneity of senescent cells and identification of a senescence-associated signature (Hernandez-Segura et al, 2017, Current Biology)
2017 Discovery that highly inflammatory (SASP positive) senescent cells are prone to anti-senescence treatment with FOXO4-p53 drugs (Baar et al, 2017, Cell)

Cleara, the company

At Cleara Biotech, we are highly motivated to develop safe and effective treatments to counter the negative aspects of aging and target diseases like therapy-resistant late stage cancer. We aim to do so by generating compounds that are capable of selectively eliminating senescent and senescent-like cancer cells. Cleara Biotech is the exciting result of a long and proven academic history of the key members of our scientific team.

Cleara in the Press

Drug 'reverses' ageing in animal tests
Purging the body of 'retired' cells could reverse ageing, study shows
Molecule kills elderly cells, reduces signs of aging in mice
Convincing Cells to Die Could Make Us Stronger
Anti-ageing: Is it possible, and would we want it?
Turning Back the Aging Clock - in Mice
The mouse that time forgot
Dutch scientists test anti-ageing molecule
Drug stops nasty chemotherapy side effects in mice with cancer
Flushing out ‘zombie cells’ could help stave off Parkinson’s, study suggests
Drug 'reverses' ageing in animal tests
Drug 'reverses' ageing in animal tests

BBC News – Drug ‘reverses’ ageing in animal tests

The Guardian – Purging the body of ‘retired’ cells could reverse ageing, study shows

Science Magazine – Molecule kills elderly cells, reduces signs of aging in mice

Discover Magazine – Convincing Cells to Die Could Make Us Stronger

BBC Future – Anti-ageing: Is it possible, and would we want it?

US News – Turning Back the Aging Clock – in Mice

De Volkskrant – The mouse that time forgot

Aljazeera – Dutch scientists test anti-ageing molecule

New Scientist – Drug stops nasty chemotherapy side effects in mice with cancer

The Guardian – Flushing out ‘zombie cells’ could help stave off Parkinson’s, study suggests

“Aging is the most dominant risk factor for the majority of diseases.”

Scientific Founder – Peter de Keizer, PhD

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Team

Peter de Keizer
Scientific Founder
Peter de Keizer
PhD
Linkedin ResearchGate
James Peyer
Executive Chairman
James Peyer
PhD
Linkedin ResearchGate
Alexandra Bause
Board Member
Alexandra Bause
PhD
Linkedin ResearchGate
Tobias Madl
Scientific Cofounder
Tobias Madl
PhD
Linkedin ResearchGate
Marco Demaria
Scientific Cofounder
Marco Demaria
PhD
Linkedin ResearchGate
Boudewijn Burgering
Scientific Advisor
Boudewijn Burgering
Professor / PhD

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Relevant papers

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ.

Cell. 2017

PMID: 28340339

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J.

Cancer Discov. 2017

PMID: 27979832

Hallmarks of Cellular Senescence.

Hernandez-Segura A, Nehme J, Demaria M.

Trends Cell Biol. 2018

PMID: 29477613

The Fountain of Youth by Targeting Senescent Cells?

de Keizer PL.

Trends Mol Med. 2017

PMID: 28041781

Therapeutic interventions for aging: the case of cellular senescence.

Soto-Gamez A, Demaria M.

Drug Discov Today. 2017

PMID: 28111332

Unmasking Transcriptional Heterogeneity in Senescent Cells.

Hernandez-Segura A, de Jong TV, Melov S, Guryev V, Campisi J, Demaria M.

Curr Biol. 2017

PMID: 28844647

Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

Kruiswijk F, Hasenfuss SC, Sivapatham R, Baar MP, Putavet D, Naipal KA, van den Broek NJ, Kruit W, van der Spek PJ, van Gent DC, Brenkman AB, Campisi J, Burgering BM, Hoeijmakers JH, de Keizer PL.

Oncogene. 2016

PMID: 26279295

An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.

Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé M, Hoeijmakers J, deBruin A, Hara E, Campisi J.

Developmental Cell. 2014. 31:722-33.

PMID: 25499914

Forkhead box o as a sensor, mediator, and regulator of redox signaling.

de Keizer PL, Burgering BM, Dansen TB.

Antioxid Redox Signal. 2011

PMID: 20626320

Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.

de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM.

Cancer Res. 2010

PMID: 20959475

p53: Pro-aging or pro-longevity?

de Keizer PL, Laberge RM, Campisi J.

Aging (Albany NY). 2010

PMID: 20657035

Mdm2 induces mono-ubiquitination of FOXO4.

Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM.

PLoS One. 2008

PMID: 18665269

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