Alpha-synuclein Picobody: A Novel Blood-Brain Barrier Permeable Diagnostic Ligand for Parkinson's Disease

Objective/Rationale:             
The presence of the blood-brain barrier (BBB) has been an insurmountable impediment to successful drug delivery to the central nervous system. To circumvent the BBB challenge, ICBI has developed Picotechnology to deliver a novel class of antibodies termed ‘picobodies’ of ~50 kDa to the CNS. Since compelling evidence have identified a-synuclein (a-syn) as a key factor in the pathogenesis of PD, we generated BBB permeable a-syn-picobody with an emphasis that any diagnostic agent must interact with pathological forms of a-syn (oligomers, aggregates and fibrils) for such agent to be clinically useful. A great advantage of a-syn-picobody is that it can serve as a positron emission tomography (PET) ligand, and used as a non-invasive imaging tool for detection and monitoring disease state in vivo.

Project Description:             
Pharmacokinetics and biodistribution of a-syn-picobody in a PD-like transgenic pre-clinical model carrying the A53T mutation will be determined. Blood and tissue will be collected from the model, injected with a single dose of a-syn-picobody at different time points, and analyzed for the amount of radioactivity present in each sample. To analyze the relationship of a-syn picobody uptake in vivo and percentage of a-syn deposits detected in vitro, ex vivo immunohistochemistry analysis of a-syn aggregates detected by a-syn-picobody in the brain tissue sections will be carried out. These assessments will demonstrate the efficiency of a-syn-picobody in reaching target area, in this case the brain; and binding to a-syn aggregates.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
The ultimate goal of this study is to utilize a-syn-picobody as a biomarker to visualized pathological forms of a-syn either as inclusions, pre-LB or LBs using antibody-based approach coupled to PET imaging. The success of picotechnology will have a significant impact on early detection especially for patients at risk before the onset of clinical decline, and monitoring of disease state in patients afflicted with PD.

Anticipated Outcome:          
We expect our study to demonstrate a greater BBB permeability of a-syn-picobody compared to conventional antibodies. We believe that the intermediate size and the presence of Fc region to be advantageous for pharmacokinetics and biodistribution of a-syn-picobody and present an excellent combination of picobody uptake and clearance for potential use as a PET ligand in vivo.