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© Anaxomics 2015

Systems BiologyMolecular cartography applied to

health and disease

Simón Perera del Rosario, MSc

Business Developer –

Communications [email protected]

@anaxomics

@SimonPerera

Academic researchers Pharmas Nutraceuticals

Clinical researchers CROs Cosmetics

Biotechs VCs and investors Veterinary industry

ANAXOMICS Company Profile

Proprietary technology

Therapeutic Performance Mapping System “Applying Systems Biology to Health & Life Science to provide solutions to the most challenging biological and medical needs“

Founded in

2007Based in

BCN20

experts

Pharmacology

Physiology

Artificial intelligence

TPMS

Service provider:

10+ FP7s

& H2020s

What is Systems Biology?

(…) the study of the behavior and relationships of all of the elements in a particular

biological system while it is functioning.A New Approach To Decoding Life: Systems Biology

T. Ideker, T. Galitski & L. Hood (2001) Annu. Rev. Genomics Hum. Genet. 2:343–72

(…) developing an understanding of how phenotypic behavior of the system as a

whole emerges from the components and interactions that constitute the

system.Systems biology—biomedical modeling.

Sobie, Eric A., et al. Science signaling 4.190 (2011): tr2.

Systems Biology – Anaxomics’s TPMS

NODESgenes/proteins

(functional information)

LINKS = relationshipsPhysical interaction

MetabolicSignaling

Databases

(…) represents an important first step, it is analogous to a static roadmap,

whereas what we really seek to know are the traffic patterns, why such traffic

patterns emerge, and how we can control them.Systems Biology: A Brief Overview. H. Kitano, Science 295, 1662 (2002)


?!

Artificial intelligence


TPMS = functional biological network + AI

NODESgenes/proteins

(functional information)

LINKS = relationshipsPhysical interaction

MetabolicSignaling

Databases

+Modelling through

artificial intelligence

(AI)

• Non-linear classifiers

• Artificial neural networks (ANNs)

• Sampling methods

• …

Mathematical model generation: More than canonical pathways

Real population Average MoA

Systems biology applied to non-alcoholic fatty liver

disease (NAFLD): treatment selection based on the

mechanism of action of nutraceuticals.

Perera, Simón, et al. Nutrafoods 13.2 (2014): 61-68.

1. Global human information

2. Disease-specific restrictions

3. Project-specific restrictions

Systems Biology – Anaxomics’s TPMSBED (Biological Effectors Database)Comprehensive, hand-curated database (Bibliographic search)

Systems Biology – Preclinical applications

Mechanism of action• Complete understanding of

input-output relationships• Identify the key proteins

Biomarkers• Filter data in the disease context • Integrate data from different sources • Identify complex biomarkers with the

highest generalization capacity• Mechanistic rationale

Therapeutic target identificationDisease-based repositioning • Non-obvious therapeutic targets• Know the best drugs and combinations to

treat a disease

Drug repositioning• Know all the diseases that your drug can treat (and

how efficaciously)• Extend patent life• Rescue failed and out-of-patent compounds

Safety & efficacy assessment• Efficacy compared to its

competitors• Know the effect of your drug over

life quality and possible safetyissues

• Screen your candidates• Human responses not observable

in animal models

In- & out-licensing• Highlight the strong points

of your drug

© Anaxomics 2014

ANN-based approachese.g. repositioning of nutraceuticals for NAFLD

e.g. applied in:

FP7 / H2020

Disease-based Repurposing Alzheimer’s disease

Parkinson disease

Amyotrophic Lateral Sclerosis

Peripheral Nerve Injury

Glaucoma

Multiple Sclerosis

Cancer

Ageing

Fatty-liver disease

Infections

Hair loss

Ulcerative Colitis

+ others Client’s projects

Drug-based Repurposing >20 pharma and biotech companies from Europe, US and Japan.

ANN based technologies – repositioning examplesN

eu

rod

eg

enera

tive

dis

ea

se

s

3 Healthy PNI

Is there any combination of approved drugs that act on the key proteins identified?

Repositioning results are validated in vivo







treat a disease







in animal models


of your drug

© Anaxomics 2014

Sampling methods-based approachese.g. MoA of L-carnitine against NAFLD

Average MoA

One of the cluster MoAs

Perera, Simón, et al. "Systems biology

applied to non-alcoholic fatty liver disease

(NAFLD): treatment selection based on the

mechanism of action of

nutraceuticals." Nutrafoods 13.2 (2014): 61-

68.

e.g. applied in:

FP7 / H2020

Relative activity level of cohort 1

(regeneration) respect to cohort 2

(degeneration)

Differential pattern of activity

between the two cohorts

Uniprot

code

Gene

Name

Effector of

neuronal

regeneration

Known effect

in neuronal

regeneration

Reference

(PMID)Evidence

P08670 VIME 19766119 Vimentin participates in retrograde transport.

P45880 VDAC2

19543220

and

20019051

It remains unknown which, if any, of the vDAC isoforms

participate in the CNS response to acute injury and it has reported

that modifications of the mitochondrial outer membrane protein

VDAC2, which was shown to inhibit the mitochondrial apoptotic

pathway, could be involved in regulating apoptosis in

Amyotrophic lateral sclerosis (ALS).

P60520 GBRL2

Cohort 1 Cohort 2

New therapeutic targets

Combinations of drugs

High-throughput Data Analysis:

Comparative MoA representation

– Cohort comparison

MoA and Key proteins

Enrichment analysis(Casas et al, Scientific Report 2015)

Enrichment analysis + Key proteins – interactome(Casas et al, Scientific Report 2015)

Non-linear classifier-based approachese.g. identifying BMs of immune protection

Objective: To find biomarkers able to predict which patients will be protected by the vaccineAX’s approach: mathematical modelling of the immunization response using microarray data. Infer biomarkers from the model.

FP7

Example of set of biomarkers to classify samples

Next Step: Identify which factors

(e.g. drug) could

transform a non-

responder into a

responder

(on going)

Strategies classifying the solutions of the models:

TPMS: classifiers according to the model

TPMS-HT: classifiers according to the

model, filtered by these proteins present

in the HT

Strategies classifying the HT:

HT: classifiers from the HT (statistical)

HT-TPMS: classifiers from the HT, filtered

by these proteins relevant in the model.

Reducing the universe of proteins

facilitates identifying a combination with

higher generalization capability.

BM panel selection from HT data

© Anaxomics 2014 21

1. Anaxomics DBs, AX restrictions & SOPs

2. Pathology & Disease characterization

3. Experimental data: microarrays EXPERIMENTAL

CONFIRMATION:

1. PCRs confirms that MoAs

created are very good

describers of Malaria

immunization (stimulated

PBMC cells)

2. BMs selected are relevant

to predict the

protected/non-protected

(confirmed by PCR in new

patient samples)

Disease Math-Models

Creation

(microarrays)

Biomarkers identification

(math-models)

Biomarker Validation

(PCRs)

Prospectively validated

In patenting process

LIST OF POTENTIAL BIOMARKERS:1. Math models: cohort 1 vs. Cohort 2:

Relevant proteins in differential MoAs protected/non-protected: 70 proteins

2. Grouping the best BM in classifiers: selected from Leave-one-out (LOO) and

generalization capabilities. NOT BY ACCURACY!!!

Systems Biology – Clinical applications

Research fields• CNS

– AD, successful repositioning

– ALS, combinations tested in vitro

– MS, MoA new compound

– MS, combinations

• Oncology

– HDAC inhibitors

– New Targets – CLL and MDS

– Repositioning – CLL and MDS

– Efficacy study for oncologic applications

• Cardiovascular

– QTc characterization

– Aging of the vasuclar system

• Diabetes and metabolic diseases

– Relationship between proteinated diet (ketosisstatus) and type II diabetes

– Repositioning for fatty liver disease: new compounds identified

• Ageing and age-related disorders

• Neonatology

• Autoimmune and inflammatory diseases

– Rheumatoid arthritis

– Periodontal Inflammatory Disease

• Infectious Diseases

– Malaria

– New antiinfectives in Gram negative

• Ocular diseases

– Glaucoma

– Acute optic nerve neuropathy

• Medical devices

– Polymeric drug impants

• Safety Biomarkers

– Predicting new early screening safety Biomarkers

• Veterinary

– Mechanism of action of drugs for new dogindications

– Repositioning - dog indication

Selected Funded Projects Competitive Public Funding

Start Year

Acronym Title CALL

2011 RAPID Rheumatoid Arthritis and Periodontal Inflammatory DiseaseFP7-PEOPLE-2011-ITN

2012 VISIONProlonged inhibition of semaphorine3a pathway via a bio-degradable implant towards a better therapy for visual sensory impairments

FP7-HEALTH-2012-INNOVATION-2

2013 SyStemAgeEarly warning signals of ageing in human stem cells and age-related disorders


2013 CombiMSA novel drug discovery method based on Systems Biology: Combination therapy and biomarkers for multiple sclerosis


2013 SysMalVacIdentifying correlates of protection to accelerate vaccine trials: systems evaluation of two models of experimentally induced immunity to malaria


2013 TRIGGER King of hearts, joints and lungs; periodontal pathogens as etiologic factor in RA, CVD and COPD and their impact on treatment strategies


2013 INDOXOptimized oxidoreductases for medium and large scale industrial biotransformations

FP7-KBBE-2013-7-single-stage

2016DoctoratIndustrial

Identificació de noves estratègies terapèutiques en la LeucèmiaLimfàtica Crònica (LLC)

DoctoratsIndustrials DI2015

2016 MicrobiotaIdentificació de nous ingredients moduladors de la microbiotahumana i animal fent ús de la biotecnologia industrial, les tecnologies òmiques i les tecnologies de big data

Ris3Cat-2015

2016 DiAICatLa diabetis com accelerador de deteriorament cognitiu i Malaltiad‘Alzheimer: abordatge i adherència

Ris3Cat-2015

2017 LiverHopeSimvastatin and Rifaximin as new therapy for patients with decompensated cirrhosis

H2020-SC1-PM-09-2016

Scientific Publications• Iborra-Egea, Oriol, et al. "Mechanisms of action of

sacubitril/valsartan on cardiac remodeling: a systems biology

approach." npj Systems Biology and Applications 3 (2017): 1.

• Herrando-Grabulosa, M., et al. Novel Neuroprotective

Multicomponent Therapy for Amyotrophic Lateral Sclerosis

Designed by Networked Systems. PLoS One, 2016, 11(1):

e0147626.

• Kotelnikova E., et al., Signaling networks in MS: a systems-based

approach to developing new pharmacological therapies. Mult.

Scler., 2015 Feb;21(2):138-46

• Badiola, N., et al., The Proton-Pump Inhibitor Lansoprazole

Enhances Amyloid Beta Production. PLoS ONE, 2013. 8(3).

• Pujol, A., et al., Unveiling the role of network and systems biology

in drug discovery. Trends Pharmacol Sci, 2010. 31(3): p. 115-23.

• Russell, R.B. and P. Aloy. Targeting and tinkering with interaction

networks. Nat Chem Biol 2008 Nov

• Pache, R.A., et al., Towards a molecular characterisation of

pathological pathways. FEBS Lett, 2008. 582(8): p. 1259-65.

Nature Chemical Biology -

Nov. 2008

(Cover) Artistic representation

of human interactome.

Produced using the analysis

package AxPathBuilder of

Anaxomics Biotech.

Systems Biology applied to

Biomedical Research: from basic to clinical research

© Anaxomics 2015

Simón Perera del Rosario, MSc

Business Developer –

Communications [email protected]

@anaxomics

@SimonPerera

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