Targeted delivery of proteins across the blood–brain barrier

Abstract

Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood-brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood-brain barrier bind ligands to facilitate their transport to the CNS; therefore, we hypothesized that by targeting these receptors, we may be able to deliver proteins to the CNS for therapy. Here, we report the use of the lentivirus vector system to deliver the lysosomal enzyme glucocerebrosidase and a secreted form of GFP to the neurons and astrocytes in the CNS. We fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to the targeted protein. This approach proved to be feasible for delivery of the protein and could possibly be used as a general method for delivery of therapeutic proteins to the CNS. fusion protein ͉ lentiviral vectors ͉ low-density lipoprotein receptor

Specific Amyloid β Clearance by a Catalytic Antibody Construct

“…Routes toward improving the IgV longevity and BBB penetration properties are available (e.g. attachment of an appropriate polypeptide tag) (47)(48)(49).…”

Nanoparticle accumulation and transcytosis in brain endothelial cell layers

“…For instance, the transferrin receptor is abundant in brain capillary endothelium, and it has been reported that coupling nanoparticles to transferrin can aid nanoparticle penetration into the BBB through the transferrin receptor mediated pathway. 16,24 Apolipoprotein E is an endogenous protein involved in the trafficking of naturally occurring LDL particles and when grafted on nanoparticles was reported to enhance BBB penetration, [25][26][27][28][29][30] though not necessarily translocation. 9 Similarly, cationised serum albumin has been reported to cross the BBB by absorptive-mediated trancytosis 1,31 and could also be used to gain nanoparticle access to the brain.…”

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

“…Vertebrate BBB cells express lipoprotein receptors, and transcytose both LDL and HDL in tissue culture (Dehouck et al, 1997;Balazs et al, 2004). Furthermore, linking peptides derived from ApoE and ApoB to other molecules can promote their transport across the BBB (Spencer and Verma, 2007;Zensi et al, 2009). However, circulating lipoproteins have never been shown to enter to the brain in vivo.…”