The overall aim is to further the understanding of the BBB in health and disease states towards the development of innovative brain delivery systems, especially for biopharmaceuticals (e.g., peptides, antibodies, etc.) and the identification of novel disease drug targets (Alzheimer’s Disease, MS, metabolic disease). The related key deliverables will be as follows: 1.Identification and validation of specific genes and/or mechanisms which are altered in brain endothelial cells in disease. 2. Generation, validation and characterisation of robust and predictive iPSC-derived BBB models: The developed models should be more reflective of the in vivo situation than existing models, in the healthy and disease states. 3. New, efficacious and safe mechanisms and technologies of brain delivery: The output of this topic should also result in an expanded and deepened understanding of the fundamental processes that underpin drug-trafficking across the BBB, which in turn can further support endeavours to elucidate novel and more efficacious brain delivery mechanisms. 4. Characterised new genetic models for the diseases of interest in this topic which are better amenable to evaluate disease-modifying agents. 5. Characterised mechanisms of neurotropic virus-mediated BBB and CNS penetration for development of selective brain delivery systems. 6. Established in silico/mathematical models in predicting BBB penetration of therapeutics (such as receptor-or carrier-mediated transcytosis for delivery across the BBB) and pharmacokinetics of biopharmaceutics in different compartments of CNS. 7. Identification of relevant translational readouts which are better amenable to elucidate the role of the BBB in the pathogenesis of neurodegeneration and could eventually lead to new targets for the treatment of the neurovascular causes of the diseases.

Major current hurdles for wide clinical use of AAV vectors are attributable primarily to: (i) host elimination by both immune and non-immune sequestering mechanisms – such neutralization by host antibody responses critically limits the possibility of repeated AAV delivery; (ii) AAVs are prevalent in the environment and hence a large proportion of the population carry AAV antibodies (up to 80%)– this pre-existing immunity renders AAV unable to infect target cells forcing substantial patient cohorts to be excluded from clinical trials. The current proposal is founded on compelling track record in the field and brings together a ‘best-with-best’ multidisciplinary team of international leading academic and EFPIA partners with complimentary expertise in gene therapy, immunology, chemistry, engineering, biotechnology, drug safety, viral vector production, regulatory and clinical trials. The overall goal is to analyse the currently available clinical data and then design preclinical and clinical studies to fill the knowledge gaps in advanced therapies development. Our main aims are to: 1) Develop improved model systems for predicting product immunogenicity in humans. This will be achieved by generating human and NHP 3D hepatic models; 2) Enhance our understanding of gene/cell therapy drug metabolism inside a host of cell types. The plan is to define metabolism of the therapeutic vector genome in different cell types to understand whether rates of degradation, episomal maintenance, or integration, and metabolic stress induced by AAV vector transgene expression vary from cell to cell. We will then adopt strategies to mitigate the loss of vector genomes and improve persistence; 3) Use diverse clinical expertise to establish the clinical factors around pre-existing immunity limiting patient access to advanced therapies therapy; 4) Engage regulators to ensure that the concepts and the data generated through this IMI programme will fill the gaps and support furture trials.

Europe faces an enormous human toll of brain disorders, with an estimated 83 million people affected, and economic costs amounting to approximately €800 billion. Drug treatments for brain disorders prove often less than effective with a lack of selective cell targeting. A failure to develop new drugs has led major Pharmaceutical companies to withdraw from CNS drug development in recent years. Methods such as Transcranial Magnetic Stimulation or Deep Brain Stimulation have displayed some therapeutic efficacy, however they are non-selective and/or invasive. It is therefore clear that with a failure of conventional therapy, a new approach is necessary, and development of new technology. NEUROPA will directly tackle this issue. An ideal treatment would be one where activity in specific implicated neuronal networks could be selectively modulated. To be relevant to human disorders the therapy should enable the long-term modulation of dysfunctional networks. For potential widespread use in patients the intervention and monitoring of effects on network activity should also be non-invasive. NEUROPA will develop a new Phytoptogenetics technology: novel Phytochromes that will enable modulation of expression of specific genes, selectively and non-invasively delivered and targeted to cortical neurons in specific cortico-subcortical loops. Novel compact laser sources and a Diffusing Wave Spectroscopy monitoring system will be developed to enable non-invasive bidirectional control of the phytochromes by two-photon excitation. NEUROPA will achieve in-lab technology validation of long-term network activity modulation and behavioural symptom alleviation in Huntington’s and Alzheimer’s disease mouse models. To achieve this, we have assembled a consortium of phytochrome engineering, gene delivery, laser photonics and detection experts, cellular, in vivo and behavioural neuroscientists, together with drug discovery expertise. We envisage progress to human use within 15 years.