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.
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.”
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
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.
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.
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.
Based on Denali (2022). Denali. Corporate Overview. PDF Investor presentation dated as of September 13, 2022; slide8/9, 08.09.2022.
When we invest into the theme of Digital Health, we are looking for platform solutions that can potentially offer a much better outcome for patients. Compared to other illnesses, degenerative brain diseases are an area of very high unmet need. A healthy brain is considered a major factor in judging quality of life.
Progress in the development of new pharmaceuticals for the treatment of the brain in aging, including Alzheimer’s disease (AD), has been extremely slow because the products of biotechnology, recombinant proteins or gene therapies, are all large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). Back in 2019, there was not a single recombinant protein that was FDA approved for the treatment of AD, or any other brain disease, wherein the drug has to enter the brain via BBB.6
The blood-brain barrier, while it is a wonderful development by evolution to protect our precious brain from damage, also keeps out medication from reaching the brain. A technology which can make the blood-brain barrier permeable with as much precision as possible could rightfully be considered a key platform enabling us to cross this last frontier, for the good of society.