Gene therapy targeting the blood-brain barrier
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Updated: Jun 20, 2025
Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics
Published on: November 30, 2012
Jakob Körbelin1, Adriana Arrulo2, Markus Schwaninger3
1Department of Oncology, Hematology and Bone Marrow Transplantation, UKE Hamburg-Eppendorf, Hamburg, Germany.
Insights
The blood-brain barrier (BBB) hinders CNS treatments. Producing therapeutic proteins within the BBB
Area of Science:
- Neuroscience
- Biotechnology
- Pharmacology
Background:
- The central nervous system (CNS) is protected by the blood-brain barrier (BBB), which restricts the passage of large molecules.
- This barrier poses a significant challenge for delivering therapeutics like antibodies, proteins, and viral vectors to treat CNS disorders.
Purpose of the Study:
- To explore strategies for overcoming the BBB to enable CNS drug delivery.
- To evaluate the potential of utilizing brain endothelial cells as in situ production sites for therapeutic proteins.
Main Methods:
- Review of existing strategies for BBB penetration, including receptor-mediated transcytosis using ligands like transferrin receptor (TfR).
- Conceptual exploration of producing therapeutic proteins directly within the endothelial cells forming the BBB.
Main Results:
- Receptor-mediated transcytosis shows promise but can be complex to implement.
- Producing therapeutics within endothelial cells offers a potentially simpler alternative for direct CNS supply.
Conclusions:
- The BBB is a critical obstacle for CNS therapeutics.
- Endothelial cells of the BBB present a viable and direct platform for in situ therapeutic protein production, facilitating CNS delivery.
Abstract:
Endothelial cells are the building blocks of vessels in the central nervous system (CNS) and form the blood-brain barrier (BBB). An intact BBB limits permeation of large hydrophilic molecules into the CNS. Thus, the healthy BBB is a major obstacle for the treatment of CNS disorders with antibodies, recombinant proteins or viral vectors. Several strategies have been devised to overcome the barrier. A key principle often consists in attaching the therapeutic compound to a ligand of receptors expressed on the BBB, for example, the transferrin receptor (TfR). The fusion molecule will bind to TfR on the luminal side of brain endothelial cells, pass the endothelial layer by transcytosis and be delivered to the brain parenchyma. However, attempts to endow therapeutic compounds with the ability to cross the BBB can be difficult to implement. An alternative and possibly more straight-forward approach is to produce therapeutic proteins in the endothelial cells that form the barrier. These cells are accessible from blood circulation and have a large interface with the brain parenchyma. They may be an ideal production site for therapeutic protein and afford direct supply to the CNS.
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