mRNA translation consists on translating the genetic code to proteins by the ribosome that is universally conserved in all cells. However, its structure presents significant differences between bacteria and eukaryotes. Partly because of these differences, the bacterial ribosome can be targeted specifically by a number of antibiotics without affecting the eukaryotic host cells. However, the conservation of the ribosome among eukaryotes complicates the search for specific drugs against eukaryotic pathogens such as certain protozoa like plasmodium and kinetoplastids. Our work along with other studies demonstrates the existence of significant structural differences between ribosomes of protozoa and mammals. Using Cryogenic electron microscopy, we endeavor to investigate such structural differences that are anticipated to affect some of the vital steps of mRNA translation, especially the initiation process, because of their position on the ribosome. 1. Thus we will focus on the structural differences in translation initiation between kinetoplastids and their mammalian hosts (i) by characterizing initiation complexes from several plasmodium and kinetoplastids species and compare them to their mammalian counterparts. (ii) We will also follow up on our previous works in solving the structures of various conventional, but also unconventional mammalian initiation complexes, in interaction with special mRNAs. 2. We will focus on the structure of protozoa-specific features characterized from elongating ribosomal complexes and (i) attempt to fish for regulators that they interact with from cell extracts. In addition, (ii) we will investigate the ribosomal structures from plasmodium at different stages of the parasite life cycle, as they vary according to the latter. Our results will significantly advance our understanding of protein synthesis regulation in protozoa and will represent a promising step in the search for more efficient treatments against these eukaryotic pathogens
Antibody-mediated delivery of therapeutic compounds to tumor cells for the treatment of cancer is a rapidly growing multibillion-euro market. One class of tumor markers, the glycosphingolipids (GSLs), are only rarely addressed in this context, due to the difficulty of obtaining antibodies against them. In this proof-of-concept program, we will develop a novel class of products — lectibodies — for the delivery of therapeutic compounds to tumor-specific GSLs. Our lectibodies are based on a naturally occurring GSL-binding protein with intrinsic tumor targeting capacity. We will rely on a proprietary phage library technology to isolate lectibodies against GSLs (or cocktails thereof). In this PoC program we will optimize and apply our technology to specifically target O-acetyl GD2, a GSL highly expressed in neuroblastoma tissues. This will enable us to generate lectibody-based therapeutics against neuroblastoma in children, a devastating disease for which the drug market is predicted to reach 118€ million in 2022. We will explore two options for further business development: a) building off of our current partnership with OGD2 Pharma (a biotech based n Nantes, France) and b)creation of a spin-off company which will license deals to several pharmaceutical partners based on pathology. We will capitalize on the expertise in launching start-ups of our principle investigator and on close links with clinicians and industry partners. Our technology has truly groundbreaking potential as, in principle, chimeric lectibodies can be developed against virtually any tumor-specific cocktail of GSLs thus opening the door for the development of novel therapies for several cancers. Thus, following the development of neuroblastoma-specific lectibodies, we foresee a wider range of future applications for our technology.
Heart failure (HF) affects 14 million people in Europe, and this number is expected to increase to 30 million by 2020. Early diagnosis of HF is essential for successfully addressing underlying causes. However, initial diagnosis is difficult in many situations so that HF is correctly diagnosed in only half of patients. Diastolic HF, that accounts for more than 50% of all HF patients, is due to abnormal ventricular stiffness which remains very difficult to diagnose. The characterization of myocardial properties remains today a challenge and there is no technique that can assess myocardial stiffness in clinical practice. Shear Wave Imaging (SWI), a novel ultrasound technique, has been shown capable of quantifying myocardial stiffness. The development of SWI for transthoracic evaluation of myocardial stiffness in patients is one of the major goal of ULTRAECHOCARDIO, the related ERC-funded project. To achieve this goal, ultrafast ultrasound imaging is developed in order to provide thousands of images per second of the heart requiring the development of complex equipment and imaging methodology. In ElastoCardioScope, a novel portable ultrasound device will be developed for non-invasive quantification of myocardial stiffness. The idea of ElastoCardioScope is to develop a simple and innovative approach for SWI that 1) quantifies myocardial stiffness transthoracically, 2) evaluates myocardial function through time-varying stiffness and 3) is cost effective. In contrast with SWI that requires costly and complex multichannel electronics and transducers, this project aims to develop a low cost and portable approach which does not rely on ultrafast imaging of the heart. The clinical proof of concept of this technology will be performed on patients with diastolic HF. This simple and low cost innovative technology will provide a clear solution to unmet medical needs and thus has great potential for take-up and use by clinicians at hospital but also in other points of cares.