The problem with the blood-brain barrier
We all get infections from time to time, a cold or tummy bug, verruca or athletes foot. Viruses, bacteria and fungi can inflict pain and swelling if allowed to multiply in or on our bodies. But there’s a last line of defence that stops these nasty critters from inflicting damage on one of our most precious organs, our brains — it’s called the blood-brain barrier.
Evolutionary wise, the blood-brain barrier has kept us alive over many generations as we have evolved alongside infectious pathogens such as viruses and bacteria. This barrier is made of a tight mesh of cells that separate blood vessels from the brain, and block everything except for a specific set of particles, and molecules such as oxygen and carbon dioxide.
We can see the damage that is done when this line of defence is breached by looking at the potentially deadly consequences of meningitis…
Meningitis is the term used to describe inflammation of the meninges, the tissue layers that surround and protect our brain and spinal cord. The inflammation can be caused by a viral, bacterial or fungal infection.
While most of the time the blood-brain barrier would keep these pathogens out, should they be allowed through they can quickly cause serious problems. Meningitis bacteria can trick the barrier into letting them through and pass from the blood into the brain. Once inside, the bacteria infect the meninges causing inflammation as the body’s immune response sets about fighting the infection, leading to symptoms such as headaches, fever and confusion. As the bacteria start to multiply, they begin to use up oxygen and release toxins that cause blood poisoning, which bring about a rash and can rapidly cause irreversible damage to our bodies and, if not treated, end in death.
So the blood-brain barrier is quite important! Indeed, growing evidence points to disruption of this barrier in the progression of many brain‐linked diseases, and it has even been suggested to play a role in the onset of conditions such as Alzheimer’s, Parkinson’s and multiple sclerosis.
But, when it comes to treating neurological conditions, the presence of this barrier also introduces an extra hurdle stopping drugs getting to where they are needed.
There are many ways that medications can be given. Much of the time they come as oral pills or capsules designed to dissolve in the stomach after they are taken. The drug is then absorbed by the cells of the gut, before passing into the bloodstream.
Dispersible tablets can take less time to act because they don’t need to dissolve in the gut and many “fast-acting” pain killers are designed to speed up this process also.
Then there are drugs delivered via an injection that work quicker still as they immediately enter the blood. Whatever mechanism used for drug delivery, once in the bloodstream, the molecules can quickly reach most of the organs of the body, but often not all of them.
In the late 1800s, Paul Ehrlich, injected coloured dyes into laboratory animals and observed that all organs became stained except the brain. This work led to the discovery of the blood–brain barrier. Today, over 130 years later, we now know that roughly 98% of small molecule drugs and virtually all large molecule drugs cannot pass through this barrier. This presents a major problem in treating neurological conditions like Parkinson’s, where this barrier can slow the translation of results in the lab into clinical success simply because the therapy cannot get into the brain.
Getting drugs into the brain
Drugs that are designed to access the brain and spinal cord should be relatively small, but they must also have a particular chemical composition to unlock the blood-brain barrier and pass through from the blood into the nervous system. In fact, these requirements are one of the reasons why people with Parkinson’s often take a drug called levodopa rather than dopamine as a treatment. While symptoms are caused by a lack of dopamine in the brain, this chemical is unable to pass through the barrier. But levodopa is able to enter the brain, and once there, it can be turned into dopamine by nerve cells.
Developing drugs that can pass through the barrier, and still have the highly selective nature so that they only interact with their target and not cause side effects, is a huge challenge in drug discovery. Of the therapies that successfully cross the blood-brain barrier, they often do so only in very small amounts — 1–4% for most central nervous system drugs — and are often rapidly eliminated.
Then there are therapies that may never cross this barrier — large protective growth factor proteins, for instance, fail to have these characteristics.
To get these therapies into the brain to where they are needed, researchers must develop new devices that can be surgically implanted to bypass the blood-brain barrier. Doing so comes with significant risks, as we have discovered, infection in the brain can cause life-changing injury. But this is a risk that the participants in some Parkinson’s trials are willing to take in the pursuit of better treatments that may slow the progression of the condition.
The recent glial-derived neurotrophic factor (GDNF) clinical trial was one of these studies. To deliver this protective protein, neurosurgeon Professor Steven Gill, designed a sophisticated new delivery system that used a process called Convection Enhanced Delivery (CED) to allow the delivery of the therapy deep inside the brain. The successful delivery of the GDNF treatment has already prompted the Renishaw drug delivery system to progress to other clinical trials for Parkinson’s.
GDNF trial — results explained
Between 2012–2017, a pioneering clinical trials programme investigated whether delivering an experimental treatment…
The future of drug delivery into the brain
Having brain surgery to get drugs where they are needed may seem a little daunting. But researchers are already looking at alternative ways to cross the blood-brain barrier in a more transient way to deliver new therapies.
A new technique called focused ultrasound (FUS) uses ultrasound beams to stimulate microbubbles that can temporarily open the blood-brain barrier in a specific part of the brain, potentially allowing targeted drug delivery.
Researchers at Columbia University went on to show that this technique has potential in the treatment of Parkinson’s — in a mouse model of Parkinson’s, using FUS to deliver neuroprotective genes and proteins in the brain partially restored the dopamine pathways, improving brain function.
The Food and Drug Administration (FDA) in the United States gave permission for the researchers to take the work forward to test the delivery of drugs in people with Alzheimer’s.
Research is moving forward to crack the problem of the blood-brain barrier, but there is still a way to go. We need to understand more about the biology of this barrier if we’re going to find effective ways around it. To help with this, a new consortium of 27 partners from the world of academia and industry have come together, coordinated by researchers at the University of Oxford, to tackle the challenge of delivering drugs across the blood-brain barrier targets treat neurodegenerative conditions.
Funded by the Innovative Medicines Initiative (IMI) the consortium will work to understand more about the biology of the blood-brain barrier, and develop innovative ways to transport drugs across it.
Progress into research that aims to safely overcome the blood-brain barrier, whether with state of the art surgical delivery systems or by using only recently discovered new techniques, is paving the way for clinical trials into new therapies for Parkinson’s. But you don’t have to wait to take part in research studies. Whatever you’re ready for, you can make a difference. Simply visit the Take Part Hub and enter your postcode to find a study near you.