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Creating an orthogonal gate to the brain

Project description

Therapeutics delivery to the brain: engineering a new brain transporter

The blood-brain barrier (BBB) makes it difficult to deliver therapeutics to the brain, limiting treatment options for illnesses such as cancer and neurodegenerative diseases. Current methods for delivering drugs across the BBB suffer from limited transport efficiency and peripheral tissue uptake, lowering the therapeutic index of drugs aimed for the brain. Funded by the European Research Council, the OBGate project proposes to create a new orthogonal receptor that can efficiently transport drugs across the BBB while being expressed only in the brain endothelium. Researchers will engineer a new BBB transporter and deliver it using a nanocarrier mimicking the way viruses enter cells. This approach has the potential to revolutionise brain transport and improve treatment options for neurological diseases.

Objective

Many impairing illnesses raging 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. 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 3 key features: high transport efficiency, high expression on the BBB, and low expression on peripheral tissues. This results into peripheral tissues acting as a sink and dramatically lowering the therapeutic index of drugs aimed for the brain. 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 in two: increasing transport efficiency with the new orthogonal receptor OBGate and 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 to unravel the key determinants of BBB transport and to build an ideal transport 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. As an example to prove the efficiency of our system we will aim to deliver biotherapeutics for the treatment of brain metastatic breast cancer. Overall, we will open a new gate to the brain that is poised to be paradigm-breaking in the treatment of neurological diseases.

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(opens in new window) ERC-2022-STG

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Host institution

INSTITUT QUIMIC DE SARRIA
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 499 136,00
Address
CALLE VIA AUGUSTA 384-394
08017 Barcelona
Spain

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Region
Este Cataluña Barcelona
Activity type
Higher or Secondary Education Establishments
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Total cost

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€ 1 499 136,00

Beneficiaries (1)

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