From LABIOTECH.eu by Gabriel Hoppen
What do shuttles, bubbles and ultrasound have in common? They are all methods that can all be used to target the blood–brain barrier and make treating brain diseases such as cancer and Alzheimer’s easier.
The blood–brain barrier is the gatekeeper to the brain. This highly selective protective sheath regulates the flow of substances in and out and prevents toxins and bacteria from entering. Whilst this function is vital for our survival, it presents a massive roadblock in delivering drugs – and treating diseases that affect the brain.
Over the past few years, several broad approaches tackling this issue have been garnering much attention. What are these, how promising are they, and how soon can we expect to see treatments in the clinic?
Stowing drugs in exosome bubbles
Over the past 10 years, exosomes have been gaining significant momentum as a drug delivery system. Originally considered cellular packages of junk, exosomes are lipid vesicles just a few nanometres wide loaded with molecular cargo. They are a way cells naturally communicate and exchange molecules.
Spun out from collaborators between the University of Oxford and the Karolinska Institute in 2016, Evox Therapeutics is a UK-based company focused on engineering exosomes for drug delivery across the blood–brain barrier. Currently, Evox is investigating over a dozen brain-targeting molecules that can be expressed on the exosome surface as a means of targeting the blood–brain barrier.
“Exosomes can cross the blood brain barrier at a decent level by themselves, without any particular targeting. But we’ve also shown that if you attach ligands to the surface of these exosomes, it then helps them target the brain, and you can improve the amount that crosses the blood brain barrier by 5- to 10-fold,” Antonin de Fougerolles, CEO of Evox, pointed out.
A significant advantage of exosomes is their safety profile. “If you think about safety, each time you give a blood transfusion, a unit of blood will contain [billions of] exosomes per unit of blood. These transfusions happen about 85 million times a year, and are actually very safe.”
To date, over half a dozen have been conducted in humans showing well tolerated single and repeat dosing. “We see it has great potential with regards to being able to deliver a whole range of drug modalities – proteins, antibodies, small molecules, siRNA, mRNA… we can load any drug class and target these to particular tissues,” he explained.
Working in the same space, ArunA Biomedical, with a key site in Greece, is developing an exosome-based treatment for stroke following observations seen in neural stem cells.
“We knew that in a [stroke] injury model, our neural stem cells had a reparative effect but that there was no integration of the cells into the brain. This, combined with a series of in vitro studies, led us to believe that there was something happening beyond the stem cells themselves,” Steve Stice, CEO of ArunA, told me.
Most recently, when it tested its candidate therapy in a mouse stroke model, ArunA showed a decrease in brain atrophy of nearly 35% compared to before treatment, and a 50% reduction in brain tissue loss; results not previously observed in exosome treatment studies. These results were backed up by further work in a pig model of ischemic stroke, preserving neural tissue and function.
Currently, intravenous tissue plasminogen factor is typically used to treat ischemic stroke. However, in order to show worthwhile efficacy, it must be administered within 4.5 hours from the onset of the stroke. Contrasting this to exosome therapy, ArunA’s candidate therapy showed neuroregenerative effects in the mouse model following administration 6–24 hours after stroke onset.