Project Portugal 2030

Summary

GoTOX will establish a systemically administrable smart dendritic NS to efficiently deliver neuroprotective therapeutics (BoNT/A LC) to the brain, from the early hours after an ischemic event (Fig. 1). Our ultimate goal is to accelerate the establishment of effective therapies for the treatment of stroke, by decreasing the excess of glutamate that initiates the pathological ischemic cascade. Additionally, we are going to explore top-notch technologies to establish a human-based neurovascular unit (NVU) organ-on-chip, emulating the stroke condition. It is hypothesized that the targeted delivery of this active protein (LC) to neurons at the ischemic site will set the basis of an innovative therapy towards stroke. This is a novel approach for the application of “deconstructed” BoNT/A with the development of a responsive and smart dendritic NS to the ischemic brain. To the best of our knowledge, this is the first-time neurotoxins are engineered to be delivered with dendrimers and were never used to specifically target CNS neurons in the context of brain ischemia. GoTOX aims to transform the therapy for stroke survivors by pioneering unique strategies, achieving the following objectives (O) monitored by indicators (I): O1: Design a smart cationic dendrimer based on a proprietary family of fully biodegradable PEG-GATGE dendrimers to serve as a vector of the selected neuroprotective therapeutic protein. I1: pH-sensitive smart dendrimer of generation (G) 3. >> Task 1 O2: Develop a smart dendritic delivery system to mediate the neurotargeted (HC) delivery of the catalytic domain (LC) of BoNT/A to be applied in stroke. I2: Efficient, safe and versatile NS to specifically deliver a neuroprotective treatment to neurons (up to 3 formulations). >> Task 2 O3: Perform in vivo studies in a relevant stroke animal model to: a) assess the biodistribution, neuronal targeting, bioactivity and biosafety of the NS formulations upon systemic administration; b) evaluate the efficacy (neuroprotection) of the delivered therapeutics after stroke. I3: Safe advanced NS for stroke therapy. >> Task 3 O4: Develop a human relevant stroke model of the NVU and validate the proposed NS. I4.1: NVU model for brain ischemia. I4.2: NS formulation validation in a humanized model. >> Task 4 O5: To manage and disseminate GoTOX, engage health value chain stakeholders, prepare transition to innovation and develop an exploitation roadmap. I5.1: Set of communication materials; I5.2: 1 Regulatory roadmap. >> Task 5 With several challenging and high-risk objectives, GoTOX is expected to revolutionize the development of drug delivery technologies and strategies for the CNS, contributing to the advancement of novel neuroprotective approaches with potential repercussions not only in stroke but also in several other neurodegenerative/neurological conditions. Overall, GoTOX provides innovation in technological (dendritic vector) and experimental (realistic 3D in vitro models) ambits with an impact in academia, industry, economy, and society.