Increasing evidence supports the existence of tau as an extracellular protein, and the concept of its trans-cellular propagation as a mechanism for the initiation and progression of Alzheimer's disease (AD). In this context, using antibodies to target tau pathology appeared as an appropriate approach to clear neurofibrillary tangles in AD models. A conspicuous amount of data has been produced by different laboratories showing reduction of tau pathology in transgenic animal models using tau monoclonal antibodies, with a different degree of success according to which epitopes were targeted. Unfortunately, conventional tau immunotherapy has achieved only incomplete clearance of tau pathology, and presents limitations in terms of potential inflammatory adverse events, long-term sustainability, compliance and costs. Also, effective blood brain barrier penetration and choice of the correct tau epitope are still subject of an open debate. In this application, we will employ scFv (single chain variable fragments), to target pathological tau. scFv are composed of the variable regions of the heavy and light chains of antibodies, joined by a short linker, preserving the epitope specificity and affinity of the parent monoclonal antibodies (mAb), but with a much smaller size and reduced chance of triggering unwanted inflammatory responses. scFv expression will be driven by viral vectors (adeno-associated virus, AAV) after intracerebral or intramuscular injection. Our published data show that intracranial administration of vectorized scFv-MC1, the recombinant version of the native anti-tau conformational mAb MC1, significantly reduces brain pathological tau species in adult tau transgenic JNPL3 mice. Here, we will try to further potentiate the therapeutic efficacy of scFv-MC1 preventing tau accumulation (prevention paradigm) and reducing established tau pathology (reversion protocol): we will employ an epitope- based dual therapy, combining scFv-MC1 with scFv directed against other tau epitopes, according to what observed in AD pathophysiology. We will also adopt a dual delivery strategy, intracranial or intramuscular, fulfilling both a proof of concept and a translational approach. Finally, our data show that microglia have a role in up-taking the scFv-tau complex and can degrade it, without an overt inflammatory response. Here, we will deepen our understanding of the role of microglia in this process. The overall objective of this proposal is to develop and characterize a novel therapeutic approach for AD and tauopathies, with the goal to advance peripheral administration of engineered anti-tau antibodies, which will have relevant translational potential.
Several studies have explored the possibility to clear tau pathology in animal models of Alzheimer?s disease (AD) using immunotherapy. Unfortunately, the therapeutic potential of antibodies to treat neurodegenerative diseases is limited due to the difficulty of crossing the blood-brain barrier (BBB) and reaching target molecules in the brain. The objective of this study is to investigate the effectiveness of engineered tau antibodies as treatment for tau pathology in transgenic animal models of AD, defining the mechanism of action of immunotherapy, and exploring a cost-effective therapeutic to translate into humans.
