Inhibition of Complement Pathways with VCP As A Treatment For Alzheimer's Disease

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Project Summary/Abstract Vaccinia virus complement control protein (VCP) has been shown to have structural and functional similarity to human complement control proteins. VCP modulates the human and rodent complement system. During the past two decades, we have studied VCP extensively in a number of preclinical inflammatory disease models including Alzheimer’s disease (AD) and spinal cord injury (SCI) and demonstrated that controlling complement mediated inflammation by VCP has significantly improved outcomes, leading to our hypothesis that VCP can be potentially used for therapeutic treatments of these diseases. AD is one of the most devastating diseases amongst the aging population in the world and the 6th leading cause of death in the US. It is well known that amyloid proteins and plaques are associated with activation of several proinflammatory mediators, especially complement components. Interestingly, ApoE genotypes that significantly facilitate A- deposit, are strongly involved in regulation of classical complement cascade. These pro-inflammatory mediators can cause damage on their own as well as working in synergy with each other, ultimately leading to neurodegeneration. Over time, the damaging role of complement components overpowers their beneficial effects as the disease progresses. As a result, complement pathways have become potential targets for developing treatments of diseases such as AD. To provide a proof of concept, we investigated the role of complement pathways regulated by VCP in AD mice model. In this model, VCP was shown to be effective in preventing memory loss. To further develop VCP as a potential treatment for AD, in this SBIR phase I study, we will aim at characterizing high qualify humanized recombinant VCP (hrVCP) and at the assessment of candidate hrVCP in animal models in a more clinical relevant manner by an independent CRO company with two specific aims: 1) To subject hrVCP to a full battery of in-house analytical characterization and stability profiling; ; Specific Aim 2: To validate our previous findings by testing efficacy of hrVCP in APP/PS1 AD models with collaboration of an independent CRO laboratory. Our milestone goals include development of active and stable hrVCP pre-formulation in Saline, production of more hrVCP if resources allow, and validation of efficacy data in AD models from a laboratory other than our own. If we are successful, PK/safety assessments and other preclinical studies of purified hrVCP protein will be the goal of Phase II studies, along with even more rigorous safety studies including in vitro cardiotoxicity, hepatotoxicity and bone marrow toxicity studies in stem cells derived tissue cells. We expect that the SBIR phase1 studies will lead to development of hrVCP for a commercial scale therapeutic approach to target the progression of neuroinflammation and neurodegeneration anticipated in AD patients.