Transcytosis in the blood-cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system.
Crossing the blood-brain and the blood-cerebrospinal fluid barriers (BCSFB) is one of the fundamental challenges in the development of new therapeutic molecules for brain disorders because these barriers prevent entry of most drugs from the blood into the brain. However, some large molecules, like the protein transferrin, cross these barriers using a specific receptor that transports them into the brain. Based on this mechanism, we engineered a receptor/ligand system to overcome the brain barriers by combining the human transferrin receptor with the cohesin domain from Clostridium thermocellum, and we tested the hybrid receptor in the choroid plexus of the mouse brain with a dockerin ligand. By expressing our receptor in choroidal ependymocytes, which are part of the BCSFB, we found that our systemically administrated ligand was able to bind to the receptor and accumulate in ependymocytes, where some of the ligand was transported from the blood side to the brain side.
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , Gainesville, Florida, USA ; Powell Gene Therapy Center and UF Genetics Institute , Gainesville, Florida, USA.
Héctor R
HR
Méndez-Gómez
Instituto Cajal, IC-CSIC , Madrid, Spain ; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia) , Madrid, Spain.
Albert
A
Galera-Prat
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , Gainesville, Florida, USA ; Powell Gene Therapy Center and UF Genetics Institute , Gainesville, Florida, USA.
Craig
C
Meyers
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , Gainesville, Florida, USA ; Powell Gene Therapy Center and UF Genetics Institute , Gainesville, Florida, USA.
Weijun
W
Chen
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , Gainesville, Florida, USA ; Powell Gene Therapy Center and UF Genetics Institute , Gainesville, Florida, USA.
Jasbir
J
Singh
Instituto Cajal, IC-CSIC , Madrid, Spain ; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia) , Madrid, Spain.
Mariano
M
Carrión-Vázquez
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , Gainesville, Florida, USA ; Powell Gene Therapy Center and UF Genetics Institute , Gainesville, Florida, USA.
Nicholas
N
Muzyczka