The “Trojan Horses” of the blood-brain barrier, a new non-invasive opportunity

Challenging the blood-brain barrier (BBB) to face brain-related diseases is now reaching a new era: enginereed iron trasporters and capsids are opening novel non-invasive opportunities in the BBB overcoming

The blood–brain barrier (BBB) is a highly specialized cellular barrier that controls, feeds, and protects the central nervous system (CNS) microenvironment. It possesses unique properties fundamental to ensure proper neuronal function and it represents the perfect gateway for the passthrough of molecules to target brain diseases.

From many years crossing the BBB with non invasive approaches has been a huge challenge, but now a new window of BBB-penetrant strategies is opening up.

Engineered transferrin and capsids, the new “trojan horses” of the BBB

The old story, never too old, of harnessing physiological mechanisms to improve an efficient integration of (pharmaco)therapies is making a big stepforward in the field of BBB penetration proving to be, again, the winning strategy.

Recently, a couple of novel approaches based on biological mechanisms made interesting progresses becoming the perfect “trojan horses” of the BBB. An engineered transferrin (DNL310 of Denali Therapeutics) has been generated to exploit the physiological mechanism for iron transport across the BBB and it has successfully reached phase 2/3 trial in the treatment of Hunter syndrome. In practice, by riding on the active transportation system of the brain, known as transcytosis, engineered drugs can cross the BBB and enter the CNS, delivering therapeutic agents to brain regions that cannot be reached in other ways.

In parallel, other researchers with the same goal are developing a new generation of gene therapies using engineered capsids to boost neuronal uptake and expression within CNS. Even though none of these gene therapy-based approaches have reached clinical trials yet, some biotechs have reported high levels of neuronal transduction and gene expression in non-human primates.

Results advancing knowledge to overcome the blood-brain barrier

Even though the general concept of using transferin receptors (Tfr1) to vehicle molecules through the BBB is quite old, the refinement of this approach during the last years has brought a few molecules into advanced stages of clinical trials. The novelty of the most updated Tfr1 therapeutic agents derives from a balanced compromise among specificity, to ensure efficient CNS targeting, capacity, to be sufficiently active to deliver an effective dose, affinity, to ensured better CNS uptake, and immune silencing to avoid unwanted immune reactions. With these advances it is reasonable to say that the BBB is no longer such a great stumbling block to overcome, turning out to be indeed a real powerful tool for the treatment of some still untreatable diseases.

By Francesca Mottarlini, Department of Pharmacological and Biomolecular Sciences, University of Milan