Creating an orthogonal gate to the brain

Introduction

Many impairing illnesses ranging from metastatic cancers to neurodegenerative diseases affect the brain. Unfortunately, delivery of therapeutics to the brain is highly challenging due to the blood-brain barrier (BBB). Despite decades of research, no safe and efficient strategy to overcome this barrier has reached clinical application.

Proposed Concept

Here we propose a concept that will revolutionize brain transport: creating a new orthogonal receptor to mediate transport across the BBB. Numerous molecules have been developed to achieve brain delivery via receptor-mediated transport. However, delivery is very limited presumably because no receptor combines three key features:

1. High transport efficiency
2. High expression on the BBB
3. Low expression on peripheral tissues

This results in peripheral tissues acting as a sink and dramatically lowering the therapeutic index of drugs aimed for the brain.

Current Limitations

The greatest limitation of current efforts is trying to solve both selectivity and efficient transport in a single delivery vehicle. Our unprecedented approach is based on dissecting this problem into two parts:

• Increasing transport efficiency with the new orthogonal receptor OBGate
• Addressing selectivity with a highly efficient targeted vehicle to express the receptor only at the BBB

Since this receptor will not bind any endogenous ligand, its properties and intercellular trafficking can be engineered with minimal alteration of brain homeostasis. This will enable us to unravel the key determinants of BBB transport and to build an ideal transport system.

Engineering the Delivery System

Selective expression of this receptor in the brain endothelium will be achieved by engineering a gene delivery nanocarrier mimicking the two-stage viral entry into BBB cells.

Application Example

As an example to prove the efficiency of our system, we will aim to deliver biotherapeutics for the treatment of brain metastatic breast cancer.

Conclusion

Overall, we will open a new gate to the brain that is poised to be paradigm-breaking in the treatment of neurological diseases.