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.
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.
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.
ICBI has established a collaboration with CIMS (Centre D’imagerie Moleculaire de Shebrooke, QC, Canada) since it was awarded the MJFF grant. ICBI scientists have provided the skills and technology required for generation of its picobody for alpha-synuclein (a-syn-pico). CIMS collaborators will provide radiochemistry for labeling of a-syn-pico, followed by determination of biodistribution and pharmacokinetic studies of a-syn-pico. Currently, we are optimizing the methodology for iodination of a-syn-pico.