Toxicogenomics study
design
CIT
proposes the following short and easy-to-perform toxicogenomics study
design for the dissection of toxic mechanism and toxicity prediction,
using dose/time combination that produces a maximal impact on gene
expression. This design may be customized to your specific objective.
- 3 animals for each sampling occasion
- 1 control and 2 test item-treated groups
- Fully effective dose
- Maximum tolerated dose
- One to three sampling occasions on a
short-time period (usually 1-14 days after treatment)
- 27 chips/tissue/organ
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Tissue sampling
Tissue
sampling is a critical point for high quality results
- Adapted sampling
procedures to ensure top level quality RNAs
- Highly trained dedicated technicians
- Experience, rapidity, design of tissue
sampling sequence by giving priority to sensitive or
target organs
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RNA or DNA
extraction
GLP
compliant nucleic acids extraction: expertise and high throughput
- 20,000 RNA extractions in last 24
months
- RNA extraction procedures for more
than 50 tissues from rodents, primates or clinical samples
- DNA extraction from blood (animals
or clinical samples) or tissues for biodistribution studies
Bioanalyzer RIN values document the high quality of extracted RNAs. |
 Agilent
Bioanalyzer profile
of high quality rat liver RNA
(RIN=9.8) |
Specific
procedures and robust RNA quality controls: the key factors for a
successful toxicogenomics approach
Ancian P., oral communication : Agilent
Technologies Satellite Symposium, Novel Approaches to Toxicological
Research, Eurotox 2005, Cracow.
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GLP compliant Real
Time PCR
GLP
compliant Real-time PCR Applied Biosystems 7900 HT Fast
with Taqman ® Low-Density Array (LDA) upgrade
- Quantification of any transcript
with a known sequence (up to 380 transcripts on one plate)
- Regulatory biodistribution studies
for gene therapy products
- SNP genotyping on
clinical samples
 Real-time
PCR Applied Biosystems 7900HT
|
 Dose
response curve of exogenous mRNA spikes in rat liver RNA
(quadriplicates) |
 Taqman®
Low Density
Array: up to 380 transcripts in one plate
|
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Studies for gene
therapy products
biodistribution
Regulatory
biodistribution studies are a pivotal requirement during the
preclinical safety evaluation of gene therapy vectors, wether viral,
naked or complex DNA. They provide essential safety data on the
persistence of the DNA in the organs and its dissemination throughout
the tissues.
CIT provides a complete biodistribution
study solution which includes:
- In
vivo phase under BSL1/BSL2 conditions
- Enhanced necropsy procedures in order to
avoid organ-to-organ contaminations
- DNA extraction from blood and tissues
- Quantitative PCR including validation of
PCR assay and DNA extraction process
- All phases of study are GLP compliant
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Microarrays
Affymetrix
platform
- Studies on whole transcriptome arrays,
including:
- Human Genome U133 Plus 2.0 (47,000
transcripts)
- Mouse Genome 430 2.0 (39,000
transcripts)
- Rat Genome 230 2.0 (30,000 transcripts)
- Canine Genome 2.0 (38,000 transcripts)
- Porcine Genome (23,256 transcripts)
- Highly trained and experimented
technicians
- Capacity to process 200 chips a week
- More than 2.000 chips processed in the
last 6 months
 CIT's
equipment |
|
 Affymetrix
arrays |
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Bioinformatics,
Biostatistics
Versatile
data analysis capabilities
- Affymetrix Raw data
delivery (MIAME compliant)
- Range of pre-processing
methods: mas5, plier, rma, mbei etc.
- Several tools available : dChip,
Arraytrack, bioconductor, SAS
- Statistical analysis
- Data filtering
- Hierarchical clustering, PCA,
correlation matrix etc.
- Ontology classification
and pathway integration
- Data format : html, excel
files or customized
- Easy understanding of compound
safety and predictive toxicity by data comparison with Iconix's Drug
Signatures® database: ToxFx
- Convenient, comprehensive and
interactive web-based presentation of results
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Guidelines
CIT studies comply with the guidance
documents, which have been issued by the regulatory agencies.
- The FDA guideline entitled "Pharmacogenomics
Data Submissions"
was released in March 2005 in order to clarify for sponsors the agency
current thinking about when pharmacogenomics data must be submitted, or
would be welcome on a voluntary basis. To date, several voluntary
submissions addressed preclinical safety issues, including
hepatotoxicity of PPARs, cardiotoxicity, vasculitis and muscle
toxicity. These voluntary submissions have been reviewed by the newly
formed FDA's
Interdisciplinary Pharmacogenomics Review Group.
- The same guideline provides a
classification of
biomarkers in the context of regulatory submission. This has been
expanded to a preclinical safety biomarker validation path proposed by
the dedicated "Predictive Safety Testing Consortium"
(PSTC), which includes as members, the FDA, the Critical Path Institute and
most of major pharmaceutical companies.
- The MAQC (MicroArray Quality Control)
study guidance and a FDA preliminary concept paper entitled "Recommendations for the
Generation and Submission of Genomic Data, Nov 2006"
are
aimed to avoid procedural bias in microarray experiments. This lead to the release in August 2007 of the "Pharmacogenomic Data Submissions - Companion Guidance".
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Short term, tolerance and
in-vitro toxicology