ERC FUNDED PROJECTS

Inherited retinal degenerations (IRDs) are a major cause of blindness worldwide. IRD patients witness inexorable progressive vision loss as no therapy is currently available. In the last decade my group has significantly contributed to a change of this scenario by developing efficient adeno-associated viral (AAV) vectors for retinal gene therapy that are safe and effective in humans. The objective of EYEGET (EYE GEne Therapy) is to overcome some of the current major limitations in the field of retinal gene therapy to expand initial therapeutic successes to a larger number of IRDs. To achieve this, we propose to use four parallel, highly innovative and complementary approaches: i. expansion of the limited AAV cargo capacity by a novel methodology based on co-administration of multiple AAVs that reassemble in target retinal cells and reconstitute large genes; ii. targeting of frequent dominant gain-of-function mutations that cause RP using state-of-the-art AAV-mediated genome editing technologies; iii. induction of retinal cells clearance of toxic IRD products by AAV-mediated activation of autophagy and lysosomal function; iv. development of methodologies to directly convert fibroblasts to photoreceptors that can be transplanted in retinas from IRD patients with advanced PR loss and for whom in vivo gene therapy is no longer an option. We will use a combination of in vitro and in vivo state-of-the-art technologies including novel AAV vector design, high content screening of drugs that enhance AAV transduction, genome editing, and advanced in vivo retinal phenotyping to obtain proof-of-concept for each of these therapeutic strategies. The results from this study may impact the quality of life of millions of people worldwide by providing a cure based on gene and/or cell therapy for a large group of IRDs.

2 499 564 €

Start date: 2017-01-01, End date: 2022-12-31

"Alzheimer’s disease is the most common form of dementia affecting more than 35 million people worldwide and its prevalence is projected to nearly double every 20 years with tremendous social and economical impact on the society. There is no cure for Alzheimer's disease and current drugs only temporarily improve disease symptoms. Alzheimer's disease is characterized by a progressive deterioration of cognitive functions, and the neuropathological features include amyloid beta deposition, aggregates of hyperphosphorylated tau protein, and the loss of neurons in the central nervous system (CNS). Research efforts in the past decades have been focused on neurons and other CNS resident cells, but this "neurocentric" view has not resulted in disease-modifying therapies. Growing evidence suggests that inflammation mechanisms are involved in Alzheimer's disease and our team has recently shown an unexpected role for neutrophils in Alzheimer's disease, supporting the innovative idea that circulating leukocytes contribute to disease pathogenesis. The main goal of this project is to study the role of immune cells in animal models of Alzheimer's disease focusing on neutrophils and T cells. We will first study leukocyte-endothelial interactions in CNS microcirculation in intravital microscopy experiments. Leukocyte trafficking will be then studied inside the brain parenchyma by using two-photon microscopy, which will allow us to characterize leukocyte dynamic behaviour and the crosstalk between migrating leukocytes and CNS cells. The effect of therapeutic blockade of leukocyte-dependent inflammation mechanisms will be determined in animal models of Alzheimer's disease. Finally, the presence of immune cells will be studied on brain samples from Alzheimer's disease patients. Overall, IMMUNOALZHEIMER will generate fundamental knowledge to the understanding of the role of immune cells in neurodegeneration and will unveil novel therapeutic strategies to address Alzheimer’s disease."

2 500 000 €

Start date: 2016-09-01, End date: 2021-08-31

The crucial role played by molecular motors in major biological processes gives a clue on the potential of these nanoscale devices for technology. Their exploitation depends on our ability to build working and robust artificial systems, and to interface them with their environment or other molecular constructs for using the motion to carry out tasks. The goal of this project is to develop the first synthetic photochemical supramolecular pumps and to apply them for performing nanoscale transport functions and macroscopic actuation. The motor modules, which rely on a functioning and affordable minimalist design based on first principles and threaded topologies, operate autonomously away from equilibrium by using light as a clean energy source, can be switched on/off chemically, and are easy to make and functionalize. Appropriately designed motors will be embedded in the bilayer of vesicles to pump molecules across physically separated places, thereby photogenerating concentration gradients. In parallel we plan to arrange the pump modules in oligomeric tracks and investigate the autonomous, directional and processive displacement of a molecule over a few nm. These linear motors will be equipped with a cargo that can be loaded/unloaded with control, yielding the first man-made molecular transporters. Finally, we will integrate the pump components in polymeric scaffolds such that the photoinduced operation of the motors produces a non-equilibrium entanglement of the polymer chains, that can be eventually unravelled by chemical stimulation. Such materials may be used to convert, store, and reuse the energy of (sun)light upon demand. All the above functionalities are unprecedented for wholly synthetic chemical structures. Their demonstration would be a landmark result in supramolecular chemistry and nanoscience, and open up radically new directions for nanotechnology, nanomedicine, and energy conversion.

2 362 950 €

Start date: 2016-10-01, End date: 2022-09-30

Jamming of hard spheres is a new critical phenomenon whose exponents are different from those of the other known transitions. These exponents have been recently computed in a mean field approximation whose limits of validity are not known. Even if their values are in very good agreement with the ones obtained by accurate numerical simulations, the deep reasons for this success are not understood. Trampolining from these results I plan to develop a theory of the large scale properties of the free energy landscape of glasses at low temperature. I will use techniques of statistical field theory and of renormalization group to identify and compute universal features. This proposal has the following goals. • We will develop a complete analytic theory of the infinite pressure limit (jamming) of hard spheres in dimensions greater than the upper critical dimensions. We will first compute analytically the upper critical dimension. Numerical simulations suggest that the upper critical dimensions is equal to or smaller than 2: this result is puzzling and it would be very interesting to find out if this indication is supported by the theory. We will also investigate in detail the scaling properties and the conformal invariance of the correlation functions. • Starting from these results we will derive universal properties of glassy materials in the low temperature regions in the classical and in the quantum regime. The properties of multiple equilibrium configurations are crucial; we will study the structure of small (localized or extended) oscillations around them, the classical and quantum tunneling barriers. • We will analyze both equilibrium features and off-equilibrium features (like plasticity and the time dependence of the specific heat). The subject has been widely discussed and phenomenological laws have been derived. I aim to obtain these laws from first principles using the properties of the free energy landscape in glasses that will be derived analytically.

1 760 000 €

Start date: 2016-06-01, End date: 2021-05-31