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The Blood-Brain Barrier: The Last Frontier?

Technology enabling the penetration of substances through the blood-brain barrier is a breakthrough development since it enables a targeted drug delivery to the brain. Due to demographic ageing, neurodegenerative brain diseases are becoming more common, so any progress in this area will offer significant benefits to patients, their relatives, and the health care system as a whole.

December 19, 2022

Thomas Amrein¹

CFA, Senior Portfolio Manager and Lead Manager of the Credit Suisse Digital Health Equity strategy

As populations age, the prevalence of chronic diseases is rising significantly. Most chronic conditions are age-related and hence, are a major consideration under any health care system. However, as many of the chronic degenerative diseases are located in the brain, they are difficult to target even by modern medicine. Progress in treatment options for diseases such as Parkinson’s, Alzheimer’s, Multiple Sclerosis, to name just three very prevalent ones, has been limited, leading to frustration on the parts of patients and their relatives.

Why has it been that medication being active in the brain has produced so many failures and setbacks? One of the reasons seems to be the existence of the so called blood-brain barrier, also referred to as the BBB, which is shielding the brain from many substances in the blood stream. While it is clear such a protection is important to the brain, it also means that medications that are targeting the brain would find it very difficult to even reach the brain in therapeutically active concentration.

"For many older people, Alzheimer's, Parkinson's, and other degenerative brain diseases become a major issue to quality of life. If we can deliver a medication to the brain, progress against those diseases might finally accelerate." Thomas Amrein, CFA, Senior Portfolio Manager and Lead Manager of the Credit Suisse Digital Health Equity strategy

What is the blood-brain barrier and what does it do?

The blood-brain barrier acts as an additional boundary between the circulating blood and the extracellular space of the brain. The barrier is highly selective, meaning it only allows certain substances to cross from the bloodstream into the brain. This functions to protect the brain from toxins, pathogens, and even circulating neurotransmitters (e.g. glutamate) that can be potentially damaging to neurons if their levels get too high. Only water, certain gases (e.g. oxygen), and lipid-soluble substances can easily diffuse across the barrier (other necessary substances like glucose can be actively transported across the blood-brain barrier with some effort).2

Sources: Credit Suisse, Christopher & Dana Reeve Foundation; based on Blood-Brain Barrier & The Spinal Cord - Blog - Reeve Foundation (christopherreeve.org), accessed 14.09.2022.

Why do we need the blood-brain barrier?

‘The purpose of the blood–brain barrier is to protect against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain.

Its other function is to help maintain relatively constant levels of hormones, nutrients and water in the brain – fluctuations in which could disrupt the finely tuned environment.

So what happens if the blood–brain barrier is damaged or somehow compromised?

One common way this occurs is through bacterial infection, as in meningococcal disease. Meningococcal bacteria can bind to the endothelial wall, causing tight junctions to open slightly. As a result, the blood–brain barrier becomes more porous, allowing bacteria and other toxins to infect the brain tissue, which can lead to inflammation and sometimes death.

It’s also thought the blood–brain barrier’s function can decrease in other conditions. In multiple sclerosis, for example, a defective blood–brain barrier allows white blood cells to infiltrate the brain and attack the functions that send messages from one brain cell (neuron) to another. This causes problems with how neurons signal to each other.’3

When do we need to get through the blood-brain barrier – and how?

The blood–brain barrier is generally very effective at preventing unwanted substances from accessing the brain, which has a downside. The vast majority of potential drug treatments do not readily cross the barrier, posing a huge impediment to treating mental and neurological disorders.

One possible way around the problem is to “trick” the blood–brain barrier into allowing passage of the drug. This is the so-called Trojan horse approach, in which the drug is fused to a molecule that can pass the blood–brain barrier via a transporter protein.

A different approach is to temporarily open the blood–brain barrier using ultrasound.4

To reach a more uniform distribution of medication in the brain, as well as for safety reasons, primarily non invasive techniques are currently targeted for development.

Sources: Credit Suisse, Italian Journal of Pediatrics; based on Possible strategies to cross the blood–brain barrier | Italian Journal of Pediatrics | Full Text (biomedcentral.com), accessed 14.09.2022.

Denali Therapeutics – a platform built around crossing the blood-brain barrier 

As a company which is working on a broad platform for brain delivery, Denali Therapeutics has entered into collaborations with Biogen, Takeda, and Sanofi.5 This should not come as a surprise, as a transport mechanism combined with an already established pathway of a drug can offer mutual benefit to both partners.

Sources: Credit Suisse, Denali Therapeutics. With their kind permission to use.
Based on Denali_Corporate_Overview_September_8_2022.pdf (denalitherapeutics.com), 08.09.2022.

As amazing as it sounds, to be able to cross the blood-brain barrier for biotherapeutics – Denali Therapeutics works on brain delivery in four different classes of medications. Each of these transportation modalities is a platform in itself, as it can potentially be applied to many different individual medications. 

Sources: Credit Suisse, Denali Therapeutics. With their kind permission to use.
Based on Denali (2022). Denali. Corporate Overview. PDF Investor presentation dated as of September 13, 2022; slide8/9, 08.09.2022. 

Conclusion

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1 The individuals mentioned above only conduct regulated activities in the jurisdiction(s) where they are properly licensed, where relevant. 
2 Know Your Brain: Blood-Brain Barrier (neuroscientificallychallenged.com), accessed 13.09.2022 
3 What is the blood-brain barrier? - Queensland Brain Institute - University of Queensland (uq.edu.au), accessed 13.09.2022. 
4 What is the blood-brain barrier? - Queensland Brain Institute - University of Queensland (uq.edu.au), accessed 13.09.2022. 
5 Denali (2022). Denali. Corporate Overview. PDF Investor presentation dated as of September 13, 2022; slide8/9, accessed 14.09.2022. 
6 Frontiers | Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain (frontiersin.org), accessed 14.09.2022.