smb cafe 13 feb '14 - good biomarker sciences, future outlook

Proximal markers

Good Biomarker Sciences

www.gbsleiden.nl

Biomarker development laboratory.

Haemostasis and inflammation models and biomarkers

Immunogenicity / toxicity

--- NEW: Disease markers

Phase I-IIa unit

Pharmacodynamic biomarkers

Amyloid research

Our model

• A research CROguided by customer requests,

and own idea’s

new biomarkers models and platforms;

be a partner in interpretation

ER ER ER UPR Inflammasome

Cellular mechanisms

ER ER ER UPR Inflammasome

high/low metabolic

LipidFFA

Glucose

virus

PAMPS/DAMPSo.a. TLR4/LPS

Specific triggers

Homocysteine (B12)

Alcohol

Hypoxia

Transfat

Palmitate

Uric acid

Peroxynitrite

glucosamine

In the cell

Mito

Pro-apoptotic

Anti-apoptotic

Markers (CRP)

Oxidation C/EBP-β (LPS, age)

Cathepsin B/D

Il-18 IL-1-beta

Chaperone reduction

NFkBearly

late

Immunity

pyroptosis

Poluttants

Asbestos

Crystals

amyloid

Not coping:Failure UPR

• Debris in the cell– Cellular death

• Activation inflammasome– Cellular death

After Hosoi, 2010

No balance anymore: debris

Final phase

Inflammasome activation

• Pyroptosis (inflammatory cell death)

• Markers: Il-18, IL-1β (pain), Cathepsins

• Auto-antibody increases

Aβ

eq

uiv

alen

ts (

fg/m

L)

Evaluation of CSF Samples: EP-AD

**

**

** 2,000

** p<0.001

1,500

1,000

500

0 Control MCI AD

N=62 N=50 N=79

Average signal 130.5 563.2 364.1

EP-AD detects aggregated Aβ in CSF of AD and MCI patients.

All 3 groups are statistically significantly distinct.

7

Overlap !

Late stage markers

• Il-18, Il-1β, Cathepsins

• Auto-antibody titers

Detection of auto-antibodies

a) Many are present (low level) from birth on

b) Disease specific patterns occur for multiple antigens per disease with an increase in titer and shift in type.

c) Example HIV-infected people are “loaded” with auto-antibodies

Fattal. Immunol 130, 2010:337.

miRNA as disease markers

Signature of tissue state and disease

Exosomes and microparticles, HDL and carriers stabilise miRNA in biological fluids

Plasma contains MPs from different origin

Plasma contains MPs from different origin

Tumor

New: MicroRNA-21

• Elevated in blood in cases with colorectal cancer

• Established as diagnostic and prognostic biomarker Natl Cancer Inst 2013, 105:849-59.

+ Functionality• Inhibition improves sensitivity to

chemotherapy.