Novel brain endothelial-targeted gene therapy vectors to treat neuroinflammatory disease

• Applicants: Professor Dr. Markus Schwaninger; Professor Dr. Martin Trepel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells ; Virology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262101348

Inflammatory central nervous system (CNS) disease like multiple sclerosis (MS) is often incurable and treatment options are frequently unsatisfactory. Therapeutic gene transfer may be a novel strategy to meet this challenge. However, like in most other potential gene therapy applications, the lack of vectors efficiently and specifically transducing the tissue of interest is the main obstacle for this endeavor. The brain microvasculature takes center stage in the pathobiology of neuroinflammation. Thus it may be a highly relevant target for therapeutic intervention. Based on an innovative approach for the selection of targeted adeno-associated viral (AAV) vectors from peptide display libraries, we have developed a novel AAV vector that transduces brain microvasculature with unprecedented efficacy and specificity after systemic intravenous administration in vivo (BR1-AAV vector). In the project proposed here, we will characterize and further improve the targeted viral capsid of BR1-AAV by subjecting it to an optimizing secondary library selection procedure. Subsequently, we will use this brain endothelium-targeted vector to treat experimental autoimmune encephalomyelitis (EAE) as an experimental disease model of MS. Hallmarks of neuroinflammatory diseases are loss of blood brain barrier (BBB) tight junction (TJ) integrity, CNS infiltration by immune cells and development of perivascular lesions. To interrupt this, we will use BR1-AAV derivatives to 1.) confer brain vascular expression of CCL2 7ND, a dominant negative variant of the chemokine CCL2 that is considered to be crucial in neuroinflammation; 2.) to knock down the CCL2 receptor CCR2 on brain vascular endothelial cells to prevent BBB TJ disruption and inhibit CCL2 secretion into the blood; 3.) to stabilize BBB TJs by endothlial expression of the TJ protein claudin-1. This project may establish BR1-AAV-derived vectors as tools to study and treat a wide variety of neuroinflammatory and potentially other CNS diseases.

• DFG Programme: Research Grants