The right tool at the right time for the right question.
Whether your objective is to qualify a hit in a mitochondrial mechanism of action or to assess the safety of your products in development against mitochondrial liabilities we can accompany your questions from the design to the execution of the experiments in respect with our company’s value : Service, Professionalism and Innovation.
We have developed assays based on technologies going from the complicated to the complex allowing to target complementary aspects of the same issue: gaining earlier confidence in mechanism and confidence in safety.
Our catalogue is constantly being enhanced, if you do not see what you are looking for in the validated assays presented here please contact our scientists (+33 442 612 828 or contact@icdd-sas.com).
Drug discovery
Mitoread : Mitochondria as a target
Mitochondrial diseases are due to the malfunction of one or several enzymatic complexes in the mitochondrial electron transfer chain (ETC). They generally result from mutations in the mtDNA affecting the organization and function of these enzymatic complexes in children.
In adults, many diseases of ageing have been found to have defects of mitochondrial function. These include, but are not limited to, type 2 diabetes, Parkinson’s disease, atherosclerotic heart disease, stroke, Alzheimer’s disease, and cancer. In addition, many medicines can injure the mitochondria.
Available assays in HTS using the Mitosafe® technology
Qualification of antioxidant properties:
- lipid peroxidation assessment
- protection against H2O2-induced oxidative damages
Available assays in HCA using the Mitostream® technology
Qualification of anti-age properties:
- ICDD has developed an in vitro model using primary human fibroblasts that allows testing the properties of molecules capable of slowing or reversing the signs of ageing in cells.
In development : A fast and novel assay for identification of agents protecting against UV-induced mitochondrial DNA damages.
Mitoselect : Disease modifying drug selection
Mitoselect is a range of disease-modifying drug selection secondary assays based on the Mitostream® technology. Chronic diseases live a persistent signature in mitochondrial behavior that ICDD’s scientist have studied and characterized. This signature can be accompanied by defects in mitochondrial functions.
Using disease-specific signatures in primary cells derived from diseased- or healthy donors, ICDD’s scientists have qualified cells that can be used to test the efficacy of leads or drug-candidates to reverse the disease-specific mitochondrial behavior pattern.
Dose response analyses are performed in both cells (healthy and diseased) to derive efficacy and toxicity potential in the same assay. With a focus on ageing and neurodegeneration several assays are currently available at different stages of development.
Co-development and partnering are sought to better serve your needs.
USER’S ADVANTAGES:
- Minimum compound requirement
- No prior knowledge of the chemical structure of the test compound required
- Dose response analysis
- High content analysis providing efficacy and toxicity profiling in a single assay
- Ideal for SAR study on lead series
- Reference compounds included upon request
- Standard operating procedures
- Full report generated within 28 days of compounds reception
Mitoscore : Drug repositioning program
Within the course of the Cellesis solution development, using the Mitostream® technology, ICDD’s scientists identified signature of mitochondrial behavior associated with the preferential activity of compounds in specific organs. These signatures (patent pending) are used to guide the repositioning of drugs in other indications.
Contact us to know more about Mitoscore.
Drug development
ICDD’s solutions provide drug developers with several advantages:
- Supporting GO/ NO GO decision with biological signatures
- Saving time and money by securing / clearing the « clinical adverse events risks » early in the critical path
- Providing insight in how to define a REMS strategy
Mitostop : Go-NoGo decision based on mitochondrial integrity
Mitostop is a fast and reliable screening assay to deselect early molecule capable of generating untolerable sie effects.
Mitostop enables “Go-NoGo” decisions based on the acute impact of a drug used at 10µM on mitochondrial integrity. When mitochondrial integrity is impaired the cell will undergo apoptosis.
Examples of drugs that show positive on the Mitostop assay include trogliatzone (withdrawn for idiosyncratic hepatotoxicity), ciluprevir (stopped in phase II due to fulgurant cardiotoxicity) and daunorubicin (an anti-cancer drug with grade 3,4 toxicities on multiple organs).
USER’S ADVANTAGES:
- Minimum compound requirement
- No prior knowledge of the chemical structure of the test compound required
- Early deselection of compounds with unacceptable toxicity liabilities
- Detailed report within 1 week
- Standard Operating procedure
- High throughput
- Cost-effective
Mitosecure : identifying mitochondrial liabilities
Mitosecure is a range of fast screening assays that identify mitochondrial liabilities.
Mitochondrial liabilities are thought to be responsible for 30 to 40% of previously unrecognized toxicities. Their documentation is part of more and more critical paths focused on the identification of drug-induced liver injuries and cardiotoxicity.
FDA and EMA have issued guidelines for the development of anti-virals that recommend securing the drugs underdevelopment from advert effects on mitochondrial DNA and function. We have thus devised several service packages to address these concerns.
- Service package 1: Anti-viral package
HCA measurement of mitochondrial DNA content
Lactic acid production
Oxygen consumption
Enzymatic activity of ETC complexes - Service package 2: The exploration package
MTT
O2 consumption
ATP production
ROS production - Service package 3: The Bioenergetic Balance Screen (BBS)
The BBS measures the integrated mitochondrial respiratory function in the living cells. It assesses, in the same cell, the oxygen consumption, the ATP production with respect to the cell viability. The assay can be performed either in glucose- or galactose-rich medium depending on the cell type used. Optional integrated measure of extracellular pH is available upon request.
The BBS is validated in HepG2 cells in which its performances in the identification of mitochondrial liabilities reach 84% and in the identification of DILI are close to 60% (Refs: posters presented at the “WPC” and “Targeting mitochondria” in 2010, sent upon request).
It constitutes a more reliable and cost-effective, alternative to the current 4 screening platforms most commonly used in combination to identify mitochondrial liabilities.
Interested in our development of the BBS in human stem-cell derived cardiomycytes? take our poll (link to poll) to let us know about your interests, problematic and focus. Contact us to join in our co-development efforts with Axiogenesis.
USER’S ADVANTAGES:
- Minimum compound requirement
- No prior knowledge of the chemical structure of the test compound required
- Screening format (1 dose, high throughput, flagging of compounds)
- Mechanistic understanding and rationalization of compound deselection
- Positive and negative reference compounds included
- Standard operating procedures
- Dose response analysis upon request
- Full report generated within 15 days of compounds reception (depending on volume)
- Optimization of IND, NDA and MMA process time
- Cost-effective
Cellesis : anticipating clinical tolerance
The cellular dynamical system using the noesis (results of perception & learning from interactions) of the cell to anticipate clinical tolerance
Cellesis uses the Mitostream® technology to generate toxicity profiles correlated with human clinical tolerance for products in the lead optimization phase.
After an initial proof of concept performed on a minimal set of 20 compounds, the Cellesis algorithm was validated with more than 50 relevant compounds to cover several range of toxicity level (from non-toxic to severely toxic) and several types of grade 3-4 adverse events : cardiotox, hepatotox, muscular disorders, neuro disorders….
Using lead optimization series, the cellesis system generates
- toxicity index for each product,
- pourcent risk of severe adverse reactions associated to the compound (correlated to adverse reaction clinically observed Pearson =0.75)
- toxicity profiles allowing the quantitative comparison of compounds
- within a chemical series → establishment of STR
- within an indication (comparing gold standard or reference compounds to the test compound)
- with comparison to a reference compounds which toxicity profile is known
- identification of nearest neighbour within ICDD’s database of reference compounds
Its predictive power toward clinical tolerance was recently independently evaluated by the DSEC at 89% in a CTE program grouping 9 big and mid-size pharmas. 10 compounds selected by the industry and blinded to ICDD’s were correctly classified with the Cellesis algorithm.
Comparison of toxicity profile of test compounds with its nearest neighbours enables an extrapolation of the typology of toxicity that it may generate in the clinic. From this knowledge, markers to follow-up the apparition and development of such adverse reactions can be put in place to monitor treatment should the benefit of treatment exceed the risk associated.
USER’S ADVANTAGES:
- Minimum compound requirement
- No prior knowledge of the chemical structure of the test compound required
- Expert response to specific needs
- Comparison of product to full database of reference compounds
- Standard operating procedures
- Dose response analysis upon a 3.5 log range spanning window of opportunity for treatment
- Full report generated within 28 days after compounds reception (depending on volume)
- Optimization of IND, NDA and MMA process time
- Accurate decision making tools providing an alternative to animal testing
- Repositioning of resources