Glioblastoma multiforme (GBM) is one of the most prevalent brain tumours and is currently incurable. Patients die from tumour recurrence after resection and chemotherapy. New treatments need to overcome two great challenges: reaching the tumour margins, where the blood-brain barrier (BBB) is intact, and eradicating glioma stem cells (GSCs), which cause tumour relapse. Targeting receptors overexpressed on cancer cells with antibody-drug conjugates (ADC) has shown great promise in cancer treatment. However, most receptors on GSCs are also present in normal stem cells. Thus, targeting these receptors with antibody-drug conjugates may lead to severe side effects. The main objective of this proposal is to develop a masked nanobody-drug conjugate with the capacity to overcome the BBB and to be activated only in the tumour to selectively target GSCs. Nanobodies have increased capacity to penetrate tissues and biological barriers but none is yet available to target the GSC marker CD133. Therefore, I will generate new nanobodies against this receptor. Subsequently, I will set up a phage display platform to develop masked nanobodies that can be selectively unmasked by tumour proteases. The masked nanobody will be conjugated to a drug and then to a BBB-shuttle peptide. A panel of conjugates will be screened in vitro for target selectivity, efficient activation and BBB transport. Finally, the efficacy of the most promising candidates will be tested in a GBM mouse model. Our unique combination will generate the first bispecific nanobody-drug conjugates targeting GSCs to treat GBM. The concept of GSC-targeting with activatable ADC may change the current paradigm for the treatment of brain tumours. Furthermore, our workflow may be applied to dramatically enhance the efficacy of other biotherapeutics with on-target off-site dose-limiting effects.

Many impairing illnesses raging from metastatic cancers to neurodegenerative diseases affect the brain. Unfortunately, delivery of therapeutics to the brain is highly challenging due to the blood-brain barrier (BBB). Despite decades of research, no safe and efficient strategy to overcome this barrier has reached clinical application. Here we propose a concept that will revolutionize brain transport: creating a new orthogonal receptor to mediate transport across the BBB. Numerous molecules have been developed to achieve brain delivery via receptor-mediated transport. However, delivery is very limited presumably because no receptor combines 3 key features: high transport efficiency, high expression on the BBB, and low expression on peripheral tissues. This results into peripheral tissues acting as a sink and dramatically lowering the therapeutic index of drugs aimed for the brain. The greatest limitation of current efforts is trying to solve both selectivity and efficient transport in a single delivery vehicle. Our unprecedented approach is based on dissecting this problem in two: increasing transport efficiency with the new orthogonal receptor OBGate and addressing selectivity with a highly efficient targeted vehicle to express the receptor only at the BBB. Since this receptor will not bind any endogenous ligand, its properties and intercellular trafficking can be engineered with minimal alteration of brain homeostasis. This will enable to unravel the key determinants of BBB transport and to build an ideal transport system. Selective expression of this receptor in the brain endothelium will be achieved by engineering a gene delivery nanocarrier mimicking the two-stage viral entry into BBB cells. As an example to prove the efficiency of our system we will aim to deliver biotherapeutics for the treatment of brain metastatic breast cancer. Overall, we will open a new gate to the brain that is poised to be paradigm-breaking in the treatment of neurological diseases.

Glioblastoma multiforme (GBM) is the most prevalent deadly brain tumour and is currently incurable. Patients die from recurrent tumours that grow from cells surviving the first round of treatment. This is mainly due to the narrow therapeutic window of current drugs and to the low permeability of these drugs across the blood-brain barrier (BBB). Targeted non-viral delivery systems have shown great promise to decrease side effects of therapeutics and to enable the transport across biological barriers. The main objective in this proposal is to generate a dually targeted nanoparticle loaded with mRNA encoding a conditionally toxic protein to treat brain cancer. The nanoparticle will be modified with two ligands: an antibody for targeting tumour cells and a peptide that enables transport across the BBB. In addition, I will develop an acid-labile coating that enhances the stability of the polyplex in blood and is released upon internalization. This coating will present the ligands in a defined orientation using bioorthogonal chemistry, thereby maximising their targeting efficiency. The chemical handles will be introduced using genetic code expansion in the antibody and solid-phase synthesis in the peptide. A variety of formulations will be screened in vitro to evaluate their stability and transfection efficiency, and BBB permeability will be assessed in a human cell-based BBB model. Subsequently, the efficacy of the most promising candidates will be tested in a GBM mouse model. The combination of a polyplex having high transfection efficiency with a sheddable coating and oriented targeting ligands is designed to generate the first efficient non-viral gene delivery system for the systemic treatment of GBM, reaching all tumour cells to provide a more efficient treatment and potentially prevent recurrence.

The People's Republic of China (PRC) gradually transitions from an export-led and investment-driven economy towards a service-led and consumption-driven economy. These upcoming reforms will affect firms that rely on Chinese goods and services, but also create new opportunities to sell goods and services to the emerging Chinese consumer market. Given the use of experimental and preferential policy treatments by the PRC over the last four decades to promote economic development, different sectors of the Chinese population and economy will have different capabilities and (dis)-advantages in the forthcoming transitions. This project will identify which population groups are heading towards prosperity and which are at greatest risk of remaining in poverty and development traps. While previous research have identified links between preferential policies and inequality, this research extends the existing studies by applying the Capabilities Approach, examining rights and social justice, which will help create a more prosperous consumer market. The varying levels of inequality, human capital, rights and social justice for the Chinese consumer market will be analyzed through club convergence and partial (meta) rankings methodologies from 1985 onwards. A development-capabilities index for different sectors of the Chinese population and economy will be developed to indicate policy makers, domestic and foreign firms, the public, and academics what the current state and potentials for the next market reforms will be. The results will be enable European, and international, firms to better target Chinese consumers and industries, and help academics develop a theoretical framework based on the Chinese preferential and experimental development experience.

The overarching objective of this Staff Exchanges (SE) program is to form an international network of organizations from Spain, Germany, Slovenia, and China, working on a joint research program in the fields of health, development economics, and anthropology. Population medicine is a new medical paradigm that aims to improve the aggregate and long-term population health by mobilizing available resources through various care responsibilities. The principles of population medicine are aimed at forcing doctors and physicians to shift from a reactive model that treats ill individuals to a proactive model that focuses on the population's health. This SE Program focuses on how economics, as a collection of theories, models, techniques, and values, might enable practitioners in providing better and more efficient treatment to the population they serve. The People’s Republic of China has become a global leader in large-scale preventive screening and the digitalization of healthcare, making essential strides towards a population medicine paradigm. 23 researchers will conduct 144 PMs of secondments in Training, Data Collection, and Research Work in the four countries to Develop an economic framework for population medicine, estimate the causal impact of renewable energy and digital telecommunications infrastructure on sustainable development outcomes, and conduct a social and cultural analysis of the effects of health and sustainable development policies on European immigrants in China. The results will enable European and international medical training institutions to develop better programs and solutions to target and improve the aggregate health of their respective societies. It will bring together these existing collaborating partnerships into an interdisciplinary consortium that synergizes the intersections of their complementary research lines of health, sustainable development, and cultural integration through the training and staff exchange programs.