Project #579

Project #579 - France

Date: 2009/07/08

Deadline: 2039/12/12

Contact

Partner search located in France
To obtain more information about this Partner Search, feel free to contact our national expert in charge of this file:
Organisation	CR 02 / OSEO ANVAR - Agence Nationale de Valorisation de la Recherche - France.
Official Representant	GANOOTE, Mr Michel
Expert	Mailhes, Mrs Marielle
Email	marielle.mailhes@oseo.fr
Address	27-31 Avenue du Général Leclerc
Postcode	F-94710	City	MAISON ALFORT CEDEX
Country	France
Website	www.oseo.fr
Telephone	+33-1-41 79 94 99	Fax	+33-1-49 24 96 21

Familiar with the European Framework Programme? YES

PROJECT

Title: CURE Tuberculosis

Acronym: TB-CURE

Project type	Small or medium-scale focused research collaborative project
Status	Planned for submission
Call references	FP7 Call 3

Priorities’ Main Research Areas	The CNRS-IEM laboratory brings together renowned experts of innate immune recognition and response, with long expertise in immunsuppression and anti-inflammatory approaches, together with an expertise in innate immune responses involved in host-pathogen recognition, including TNF/LT and TLR/MyD88/IL-1R pathways in mycobacterial infection. The IEM teams made important contributions to the role of cytokines such as TNF, IL-1, IL-17 in airway inflammation and allergy, as well as on the role of TNF, IL-1 and Toll-like receptors in TB infection. It is also specialized in inflammation models, including lung inflammation, fibrosis and sepsis, and has recently deciphered novel activities of IL-1/inflammasome, but also IL-17 pathways in these pathologies. We established acute and chronic infections studies as well as a short version of a novel TB reactivation model (Cornell) in mice. The laboratory has established all the relevant techniques to analyse host resistance and immunological resistance including microscopy. We have established all the methods to investigate novel TB drug substances in vitro and in vivo in acute or chronic infection using gavage or parenteral injection and use isoniazide and rifampicin as standard controls.
Workprogramme Topic (according to each priority workprogramme)
Project description Aim: Select among several novel chemical leads from our consortium the most active compounds for in vitro killing of mycobacteria, inhibiting in vivo replication and eradicating chronic infection. Test candidate compounds in novel mouse models. Optimize for oral bioavailability by chemical modification and galenical development. Investigate combination therapies with existing TB drugs. Test safety, stability and metabolism and plan clinical study. In conclusion, novel TB chemotherapeutics will be developed to cure both active and latent TB infection in an intense combination therapy with existing drugs aiming to reduce treatment to 2 months and to circumvent the development of multidrug resistance (MDR). The objectives to achieve this goal are: Optimize three lead compounds; Confirm their in vitro TB killing activities; Test their in vivo efficacy in aerosol TB infection in mice comparing and combining with existing TB drugs. Testi oral absorption and investigate ADME, prepare galenical formulation and stability of the most active oral candidates; Test candidate compounds in a novel TB model of necrotic granuloma and in a novel therapeutic approach of chronic/latent infection with steroid induced reactivation combined with high dose chemotherapy; Investigate safety of novel compounds  using  toxicology and mutagenesis studies, and prepare early clinical studies.
Keywords	tuberculosis, drug development, lead optimization of TB promising candidates
Partners already involved
Project budget (for the running projects)	nc	Budget reserved for SMEs	nc

Research topics

• HEALTH.2010.2.3.2-2: Lead optimisation and latepreclinical development in tuberculosis (TB) drugs. - FP7-HEALTH-2010-SINGLE-STAGE

Profile of SME sought

Role	technology development, research, demonstration
Country /region	European Union
Start of partnership	start-up phase
Expertise required	The selected two compounds with the most promising profile to be a drug candidate swill be tested for ADME and Safety, which are required for a further decision point prior to phase I studies: ADME studies: The oral absorption and bioavailability of the TB-CURE compounds need to be known in order to decide the dosing interval and potential accumulation of the compounds. The distribution, metabolism and elimination of the parent compound needs to be characterized. The studies can be conducted in rodents and the metabolism can in addition be tested on human plasma in vitro with or without the addition of liver microsomes. Analytical procedures to detect the parent compound and metabolites need to be established. Therefore we need an expert on pharmacokinetic and metabolism which has the track record to be able to detect drugs and metabolites in plasma. Safety studies Potential drug candidates need to undergo a well defined battery of safety studies, which include Ames and other assays to exclude a mutagenic potential and at least a 4 toxicity week study in rodents at three doses to define a non-toxic dose prior to a phase I trial. An expertise is required to design and conduct such safety studies which are mandatory by the health authorities. Drug development companies