Novel Therapeutic Agent for Reversing Vascular Dysfunction in Alzheimer's Disease

Revised Project Summary :Alzheimerandapos;s disease (AD) is the most common form of neurodegenerative disorder associated with aging. One of the hallmarks of this disorder is the progressive loss of neuronal cells, which ultimately becomes fatal. Several lines of investigations implicate the role of vascular dysfunction, characterized by the loss of mural cells (pericytes) and compromised blood-brain-barrier, in pathogenesis of AD. Academic collaborators and founders of AivoCode Inc., the applicant company, have employed unbiased screening with in vivo phage display to probe specific vascular signature present in the brains of transgenic AD mice. This new approach to AD studies has generated a new and understudied therapeutic target that binds extracellular matrices and cell surfaces including brain vasculature in AD mice. In this Phase I application, we propose to screen recombinant antibodies against this novel target to neutralize its activity in mouse models of AD to reverse vascular dysfunction and test if it leads to slower disease progression. The results of this study will serve as stepping-stone for the company to develop a therapeutic candidate for AD.PROJECT NARRATIVE Vascular dysfunction has been implicated in pathogenesis of Alzheimer’s disease (AD). We have identified a protein CTGF, abundant in AD brains, that possibly plays a role in vascular dysfunction. In this application, we propose to identify single domain antibodies for blocking CTGF activity as therapeutic agents to reverse vascular defects and slow Alzheimer’s disease progression. This study addresses an underserved medical area, where there is a pressing need for new therapeutic advances.