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Intelligent Systems for Personalized Medicine

ISyPeM II

Prof. Carlotta Guiducci
École polytechnique fédérale de Lausanne

enrico.accastelli@epfl. 1
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rug concentration monitoring is highly critical

Imatinib exposure
(ng/ml)
time after dose (hrs)
Courtesy of N. Widmer

enrico.accastelli@epfl. 2
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es of medical treatment for which monitoring is highly critical

IMMUNOSUPPRESSIVE
DRUGS

Imatinib exposure
(ng/ml)
Patient

CANCER TARGETED
THERAPIES
time after dose (hrs)
Courtesy of N. Widmer

IV ANTIBIOTICS

enrico.accastelli@epfl. 3
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es of medical treatment for which monitoring is highly critical

IMMUNOSUPPRESSIVE
DRUGS

Imatinib exposure
(ng/ml)
Patient

CANCER TARGETED
THERAPIES
time after dose (hrs)
Courtesy of N. Widmer

IV ANTIBIOTICS

Immunoassays
(FPIA,
CMIA, MIA)
enrico.accastelli@epfl. Abbott "Architect ci8200" 4
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es of medical treatment for which monitoring is highly critical

IMMUNOSUPPRESSIVE
DRUGS

Imatinib exposure
(ng/ml)
Patient

CANCER TARGETED
THERAPIES
time after dose (hrs)
Courtesy of N. Widmer

Only
Qualitative!
IV ANTIBIOTICS Drug
concentration
needs to be
quantified with
Syva RapidTest®
15% accuracy
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for TDM
Intelligent Systems for Personalized Medicine
ISyPeM II

Administration and monitoring of medical treatments

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Intelligent Systems for Personalized Medicine
ISyPeM II

Administration and monitoring of medical treatments

enrico.accastelli@epfl. 7
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es of medical treatment for which monitoring is highly critical

IMMUNOSUPPRESSIVE
Towards distributed bioanalytics
Physiological parameters, DNA
DRUGS analysis
Hand-held

CANCER TARGETED Accu-Chek product
THERAPIES iSTAT, Abbott lines.
Roche Diagnostics
Top bench

IV ANTIBIOTICS
Clonit
cobas® Lab-in-a StMicroelectronics
tube
Roche
enrico.accastelli@epfl. 8
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Intelligent Systems for Personalized Medicine
ISyPeM II

Molecular assays needed. Lack of molecular
probes.
Sample-to-answer devices.

Compact, affordable analytical systems.
Measurement performed at the MD integrated with
decision support software

BIOCHEMICAL/ANALYTICAL CHALLENGES
Data management challenges. Gather data for
decision on dosage and enrich population data.

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Lack of availability of ligands for drug
molecules
TOBRAMYCIN

• Drugs are small molecules

• They can have very different solubility and
biochemical and metabolic characteristics
IMATINIB

• In vivo raised antibody against drugs have
poor affinities and in some case are not
available at all
TACROLIMUS

We developed in vitro approaches for
the selection of ligands for different
classes of drugs
enrico.accastelli@epfl. 10
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- NNN...NNN -

460 possible variants

In vitro selection of aptamers
=
1.33 ∙1036 sequences
Streptavidin-coated
magnetic beads Docking region (12nt)
CCTTACCTAGGTGTAG- 5'
Guiducci Lab
TOBRAMYCIN

In vitro selection results
 DNA aptamers can
Clin. Pharmac.
be obtained in a
- CCTTACCTAGGTGTAG- 5'
5' - GGAATGGATCCACATC-
few steps that are
(A) Loading
Conversion to ssDNA (B) Selection better or equal to
conjugation beads-aptamers exposition of the small
molecule to the aptamers' pool
(C) Partitioning
Separation of binding existing RNA
Binding aptamers - drug aptamers from the pool
aptamers
IMATINIB

 Functional in serum
and proved on
patient samples,
R2=0.993 meeting the clinical
LOD=0.15 µM range

 Specificity
demonstrated
Spiga F. M. et al. ACS Comb. Sci. 2015,
featured on the cover of May Issue
 Method can be
enrico.accastelli@epfl.
applied to different
11
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Measuring Tobramycin concentration
from serum on a palm-sized devices
TOBRAMYCIN

 DNA aptamers are
stable and functional
on surfaces

 Sensitivity is
demonstrated in
undiluted serum
Guiducci Lab
undergoing minimal
sample treatments

Clin. Pharmac.

G. et al. Analytical Chemistry, April 2015 . Contributed by EPFL, CHUV and STMicroelectronics

enrico.accastelli@epfl. 12
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In vitro selection of peptides
Heinis Lab
TACROLIMUS

J-M Segura
 First in vitro
selection of
antibodies
against
Tacrolimus ever
performed

 Two approached
deployed to
competition
assay

 Peptide
macrocycles-
C. Heinis, Bicyclic peptide phage display, basedThe
10th Peptide Therapeutics Symposium, 23.10.2015, approach
Salk Institute, La
enrico.accastelli@epfl. 13
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for assays
Affordability of the analytical system
Meet the microsample challenge Renaud Lab

J-M Segura
M Geiser

20 cm

25 cm
Immunoassays
(FPIA,
CMIA, MIA)
Abbott "Architect ci8200"

enrico.accastelli@epfl. 14
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Affordability of the analytical system
Meet the microsample challenge Renaud Lab

J-M Segura
M Geiser

Immunoassays
(FPIA,
CMIA, MIA)
Abbott "Architect ci8200"

ISyPeM II demonstrator
Low-cost
Fully integrated
Based on High sensitive FPIA
Works on capillaries
enrico.accastelli@epfl. 15
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Microsample analytics in capillaries

FPIA of Tobramycin performed in glass
microcapillaries Therapeutic range
Squared glass capillary
reference system
capillary

Renaud Lab
300 µm

http://dbs-system.ch

J-M Segura

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Microsample analytics in capillaries

Plasma extraction from whole
blood

Yield outperforms any passive on-chip Renaud Lab
method reported to date. Extraction
from ejection.

http://dbs-system.ch

enrico.accastelli@epfl. 17
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Drug decision support system
developed by ISyPeM II partners
Yann Thoma
 Now in use at
CHUV and
connected with
Div. Clin. Pharmac.
MOLIS database

 Largely
outperforming
any existing
support systems

 Validation and
Clinical trials in
progress for
certification and
FIT grant for start-up creation: commercializatio
http://www.fondation-fit.ch n

Lab Innovation Award, Lausanne 2016

enrico.accastelli@epfl. 18
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P2P approach for data storage

Cryptographic
Module LDB
metadata RSDB
Contributor
Anonymization
LDB
Module
Initiator
RSDB Query/Ex A1
change
Data Negotiat
e
RSDB
Tuple-center Contributor

 No centralized
system for
data storage
 Contributors P2P Network "Multi-Agent System for Dynamic Data
Aggregation in Medical Research”  A.
can share Dubovitskaya, V. Urovi, I. Barba, K.
Publish/Subscribe
their data and Aberer, M. I. Schumacher, in preparation
Dubovitskaya, A. Privacy Preserving
get Interoperability for Personalized
anonymized Medicine, in: Swiss Medical Informatics,
Swiss Society for Medical Informatics,
data from the Switzerland, 2014, Contributed by AIS
enrico.accastelli@epfl.
others Lab, Thoma Lab and CHUV 19
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Building population pharmacokinetics
models
IMATINIB

Div. Clin. Pharmac.
AMINOGLYCOSIDES EFAVIRENZ

 Consolidation of
population studies for
TDM

 Statistical combination
of independent
population studies

Br J Clin Pharmacol. 2014
Nov;78(5):1090-101
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Output and outlook

More than 15 peer reviewed papers published (only ISyPeM II)

CTI on going with a Pharma company (Debiopharm International)

nterest in the diagnostics field

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