Clever delivery
How the Brainshuttleᵀᴹ technology opens up new options for delivering medicine to the brain
The blood-brain barrier is a vital piece of our physiology that helps protect one of our most critical organs from foreign invaders. Unfortunately, its effectiveness also means that it is very hard to get medicines into the central nervous system to help treat diseases in the brain. This problem has stumped drug developers for decades, and it has long been accepted wisdom that therapeutic concentrations of biologics in the brain will always be low.
Starting in 2008, however, scientists at Roche decided to challenge this conventional wisdom, and began building a platform that could help transport medicines safely across the blood-brain barrier. Some might have thought the project too risky, or too unlikely to succeed, throughout the journey that followed. Yet through dedication and design, the team at Roche ultimately delivered a new way for medicines to cross the blood-brain barrier that is now in clinical trials: the BrainshuttleTM technology.
“At first, everyone was on the fence,” recalled Niels Janssen, Senior Principal Scientist in Pharmacokinetics and Pharmacodynamics in Roche’s Pharma Research and Early Development (pRED). “But now the BrainshuttleTM technology has created enormous momentum in the industry. We’ve flipped the conversation from if it works to how well it works.”
The Brainshuttleᵀᴹ technology has created enormous momentum in the industry. We’ve flipped the conversation from if it works to how well it works.
The BrainshuttleTM is a fragment of an antibody that interacts with cell-surface receptors on the blood-brain barrier which lines the capillaries of the brain. This interaction leads the BrainshuttleTM — and its therapeutic cargo — to be engulfed into and transported across the cells that make up the barrier, and enter the brain parenchyma, the core substance of the brain. Thanks to this and due to the dense network of capillaries in the brain, the BrainshuttleTM and its cargo can penetrate deep into the brain and more equally distribute therapeutic molecules across all brain regions. “This can also potentially help the therapy to act more quickly," said Roberto Villaseñor Solorio, Principal Scientist in Neuroscience and Rare Diseases, pRED.
Achieving this success wasn’t usually obvious or easy, however. “Over time there were ups and downs, and we had to look closely at the details to make the case,” said Jens Niewöhner, Senior Principal Scientist in Large Molecule Research in pRED, who has been on the BrainshuttleTM technology team since its inception. Two key successes for developing a successful platform were finding the right cell surface receptors and the right molecule design.
Over time there were ups and downs, and we had to look closely at the details to make the case.
In addition to figuring out how to avoid having the shuttle (and its valuable payload) being denied passage by the barrier, a critical component of the BrainshuttleTM is a portion of the molecule that can be tuned to engage with the immune system. This feature can help to clear away unwanted disease-related material, potentially without provoking unwanted immune responses outside the brain.
The BrainshuttleTM technology is also adaptable in other ways. For example, it is already possible to attach the shuttle to different kinds of therapeutic molecules and thereby opening up now ways of delivering these to the brain. In addition to traditional large molecules like antibodies, BrainshuttleTM might also carry enzymes, oligonucleotides, or enable the delivery of specific gene therapies. “This variety of potential modalities is exciting, because it will enable the BrainshuttleTM to also pursue intracellular targets,” said Felix Schumacher, Leader in pRED’s Drug Delivery Systems & Genomic Medicine department. “If we can get this to work then the sky would be the limit — this throws open the doors to very different potential treatments we can offer,” Felix added.
If we can get this to work then the sky would be the limit — this throws open the doors to very different potential treatments we can offer.
With deep knowledge in both the BrainshuttleTM technology and these other kinds of modalities, Roche is poised to develop these therapies from start to finish with in-house expertise.
Making a difference for patients
Changing intrathecal injection to peripheral administration [e.g. intravenous or subcutaneous injection] would mean reducing the treatment burden for patients and could revolutionise their care journey.
Being able to deliver different kinds of therapies directly to the brain also has the potential to make receiving therapy much simpler for patients. Right now, certain central nervous system therapies must be delivered through injection into the cerebrospinal fluid (intrathecally). By contrast, the BrainshuttleTM can be delivered intravenously into the bloodstream, like many other large molecule therapies. “Changing intrathecal injection to peripheral administration [e.g. intravenous or subcutaneous injection] would mean reducing the treatment burden for patients and could revolutionise their care journey,” said Roberto.
“For central nervous system (CNS) disorders, the BrainshuttleTM technology could be a gamechanger. This is the therapy of the future, and Roche is at the forefront,” Felix summarised. “But even more importantly, the BrainshuttleTM technology has the potential to transform and shape how brain research and research on CNS diseases is done by the entire scientific community going forward.”