Objective/Rationale:
Hindering drug development for neurological diseases like Parkinson’s disease is a lack of robust drug delivery strategies that can target medicines to the brain noninvasively via the bloodstream. Such noninvasive delivery is complicated by the presence of the blood-brain barrier (BBB) in vivo. The BBB is made up of a unique class of endothelial cells that render the blood vessels of the brain impermeable to most small molecule pharmaceuticals as well as to all gene and protein medicines. Therefore, drugs in the bloodstream have little chance of accessing their brain target.
Project Description:
Recently, a proof-of-concept noninvasive delivery strategy based on antibody targeting of endogenous BBB nutrient transport systems was shown to permit transport of drug cargo from the blood into the brain. Antibodies are linked to a drug payload that can include small molecules, proteins, DNA or nanoparticles and the antibody-drug conjugate acts as an artificial substrate for the transporter and transcytoses across the BBB into the brain. We will identify new BBB-traversing antibodies having improved brain specificity by mining large collections of antibodies that can be thought of as in vitro immune systems.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Newly identified BBB transcytosing antibodies will have the potential to allow peripheral delivery of a wide range of drug cargo including gene therapeutics or trophic proteins like GDNF. Moreover, because of the novel antibody selection methods used, these antibodies are predicted to have better targeting and delivery attributes allowing for more efficient administration of Parkinson’s therapeutics.
Anticipated Outcome:
Through the proposed research, it is expected that approximately five to 10 new antibodies that undergo transcytosis will be identified, and in contrast to current antibody-based delivery systems, these antibodies will have improved levels of brain-specific targeting serving to selectively increase the brain uptake of drug.
Final Outcome
During this project period the laboratory was successful in identifying potentially novel antibodies that may bind or target the blood brain barrier and traverse into the central nervous system. These antibodies must now be confirmed using in vivo techniques.