Electrical stimulation combined to molecular approach is a promising way for the reformation of damaged neural circuit in the central nervous system after a lesion or a neurodegenerative disease. Placing neural stimulators all along the reforming circuit is certainly key for the complete re-innervation. However, the current tethered neural stimulation technologies do not allow to position the implants over several centimetres in a custom way because of their large spatial clutter. Thus new implantable neurostimulation technologies must be developed to meet this need. In order to fill this gap, the present project suggest to create wireless and battery-free stimulators powered by ultrasound. In order to reach dimensions below 200µm required for intracerebral implants, the consortium will fabricate and use piezoelectric micromachined ultrasonic transducers coupled to stimulating microelectrodes. This new concept of wireless and battery-free electric neural stimulator will be tested in vitro on retinal explants, a gold standard to study axonal regeneration.

Ventricular arrhythmias (VAs) account for the vast majority of the 250,000 cases of sudden death recorded in Europe each year. VAs occur mainly in patients with cardiomyopathy. Intra fibrotic electrical reentrant circuits are the dominant electrophysiological mechanism. Catheter ablation is the main option for invasive treatment, involving destruction of the slow conducting channels within the scar to block the electrical circuits. Challenges related to adequate catheter placement over the target area, sufficient energy diffusion into the tissue, and lack of intramyocardial dynamic mapping result in only 30-50% of patients experiencing freedom from recurrence after ablation. The aim of the CALAMAR (ChemicAL Ablation and Mapping of ARrhythmias) project is to evaluate the use of ultrasound to 1) Map the myocardium during ablation procedure using electromechanical wave imaging (EWI); 2) Validate a disruptive strategy of "chemical" ablation combining microbubbles and ultrasound to open the blood-myocardium barrier, and lipid nanoparticles loaded with cardiotoxic agents to induce a chemical dechannelization.

Since December 2019, the novel coronavirus (SRAS-COV2, causing an emerging infectious disease called COVID-19) has spread quickly worldwide. As of Mar 16th 2020, 165 000 cases and 6 500 deaths have been reported over 146 countries (WHO data). In Europe, Italy, Spain, France and Germany are currently the countries with most reported cases and deaths (mortality ranges from 1.4% to 3.6% of cases confirmed). The main symptoms of COVID-19 include febrile respiratory infection, respiratory difficulties and, in most severe cases, acute respiratory distress, acute renal insufficiency or multi-visceral deficiency leading to death. To date, epidemiological studies have not focused on specific subgroups despite mortality seems to be much higher in frail persons. During similar previous epidemics (eg A(H1N1)pdm09) different from seasonal influenza, more severe respiratory disease and higher specific mortality were reported, especially in patients with cancer or immunosuppressed populations. Pneumonia has been reported more frequently in patients with hematologic malignancies than those with solid tumors (55% vs 25%) and the 30-day mortality is higher in patients with pneumonia (up to 26%). For COVID-19, lethal cases are mostly patients >60 (80%) with associated conditions such as cardiovascular problem, diabetes or cancer. In recent reports, an over representation of patients with cancer active treatment or cancer in remission was observed in patients with COVID-19. While all efforts are now being conducted to prevent the epidemic spread in our country, it is likely that more cases will be diagnosed in the coming months. The population of patients with cancers in active treatment (cytotoxics, immunotherapy, targeted therapy) was estimated to be close to 250 000 yearly in France (0.37% of the French population) [e-cancer.fr]. This is a large population of French citizens, who will be potentially affected with COVID-19, and represents a population at risk of life-threatening complications. In this context, blood parameters are closely followed up in patients with cancer as there is a straight relationship with treatment toxicity and patients’ outcomes. For cytotoxic chemotherapy, febrile neutropenia is observed in 5-90% of patients depending on the regimen used. Lymphopenia is frequently observed in patients with cancer and early lymphopenia correlates with the risk of febrile neutropenia and early death. Febrile neutropenia is a frequent and life-threatening complication, often associated with respiratory tract infection, which confers severity and a need for hospitalization. In onco-hematology, hypogammaglobulinemia is well-known to reduce immune function. Patients with decreased levels of gamma globulins have lower antibody counts, and an increased risk of infection. We hypothesize that patients under active anti-cancer treatment are at higher risk to develop severe complications. It is likely that this risk is different from the type of treatment and it is necessary to assess the differential impact. We propose a national collaborative study to describe retrospectively and prospectively the clinical outcome of patients with a suspected coronavirus infection (either confirmed or not) while receiving a medical anticancer treatment, including corticotherapy. Patients under anticancer treatment who have underwent a diagnostic test for the COVID-19 will be included. The 2-month mortality will be described in both groups (positive and negative cases) to assess the over-risk of mortality, adjusted on main clinical characteristics, the treatment and the type of cancer. Secondary objectives will be to describe the patients’ characteristics, the associated complications, the hospitalizations and to identify predictive factors for mortality. All patients (positive and negative) will be included from all the French Comprehensive Anticancer Centers (UNICANCER), retrospectively (from Jan 1st 2020) and prospectively a soon as the study is activated.

Presbyopia is the loss of accommodation affecting any individual after the age of 45 and preventing close reading. Although its consequences have been known and corrected by converging glasses since antiquity, biological aging, which modifies the biomechanics of the lens and makes it lose its flexibility, has only recently been understood. To date, no one has developed a treatment that restores the natural biomechanical properties of the aging crystalline lens. The expertise in focused ultrasound applied to ophthalmology is a very strong point of our territory. Also, by bringing together 2 laboratories and 2 industrial partners with major scientific expertise in ophthalmology, ultrasound, cell biology, biochemistry, optics, biomechanics and engineering, we are equipped to meet this ambitious challenge through PRESB-INNOV-US: moving towards a radical paradigm shift to overcome (finally)presbyopia.

Dependence receptors (DRs) are transmembrane receptors which trigger apoptosis in the absence of their ligands. They have been shown to act as conditional tumor suppressors (Mazelin et al., Nature, 2004; Mehlen and Puisieux, Nat Rev. Cancer, 2006; Mehlen et al., Nat Rev. Cancer, 2011, Castets et al., Nature, 2012). It has been proposed that aggressive cancers may block the apoptosis induced by these receptors by up-regulating the ligand of these dependence receptors and that an appealing therapeutic strategy could be to block the ligand/receptor interaction. This has been demonstrated for the pair netrin-1/netrin-1 DRs (Mehlen et al., Sci. Signal. 2011; Mehlen et al., Nat Rev. Cancer, 2011). The preliminary results have confirmed the hypothesis that the increased expression of ligand could occur for other DRs and as such targeting ligand/receptor interaction may be proposed for other pairs of ligand/DR. The Sonic Hedgehog (SHH) signalling pathway is believed to play an important role in the development of several cancers, including prostate, colon, pancreas and brain cancers. Drugs targeting the downstream “canonical” signaling of SHH have been developed as exemplified by the Smoothened (Smo) inhibitor GDC-0449 (Metcalfe et al. Cancer Res., 2011). However, while these drugs appear to have some efficacy in a restricted number of cancers with mutations in the canonical pathway –Smo, Ptc, Gli-, they turned to be ineffective in other solid tumors where Hedgehog ligand is yet detected. The rational of this project is that SHH expression detected in a wide fraction of cancer is not a mechanism to activate the Smoothened-Gli canonical pathway but rather to block apoptosis induced by a recently discovered dependence receptor named CDO (Cell-adhesion molecule-related/Downregulated by Oncogenes, also named CDON). Recent unpublished but patented work achieved by the academic and the valorisation partners has (i) identified the receptor CDO as a SHH dependence receptor, (ii) shown that SHH expression in various cancer cells is a mechanism to block CDO pro-apoptotic activity and (iii) provided evidence that inhibiting SHH/CDO interaction is associated with tumor cell death in vitro and tumor growth inhibition in vivo independently of the classic Smoothened-Gli pathway. As a consequence, the main objective of the present proposal is to finalize the demonstration that pharmacological targeting of CDO to block CDO/SHH interaction is an efficient targeted therapy in cancers with high SHH expression, and to develop an anti-CDO drug candidate up to phase I clinical trial. The different tasks will then be: (i) To generate a human or humanized anti-CDO monoclonal antibody (mAb) blocking SHH/CDO interaction and to provide the animal proof-of concept that this antibody shows potent anti-tumor effect in animal models. (ii) To develop a manufacturing process, including fermentation and purification steps, for the production of the required amount of anti-CDO mAb required for regulatory pharmacology and toxicology studies. (iii) To complete a preclinical package including regulatory pharmacology and toxicology studies to determine the safety profile of the anti-CDO mAb and guide dosing in Phase I clinical trial. (iv) To identify the putative eligible responding population by analyzing SHH as well as CDO expression in human cancers. (v) To draft a clinical trial authorization application including key regulatory documents such as the investigator’s brochure and the study design of the phase I clinical trial to be conducted in patients with advanced cancers of various histology, selected for their expression level of SHH and CDO.