Breaking the blood-brain barrier: neurology’s greatest challenge

Evolution has gone to great lengths to protect the human brain from damage. A barrier between the brain’s capillaries and its other components, known as the blood-brain barrier, exists to provide a defence against disease-causing pathogens in the blood. In the capillaries that form the blood-brain barrier, endothelial cells are packed in together, forming tight gaps, which only allow small molecules, fat-soluble molecules and some gases to pass through. 

As well as protecting against potentially infectious substances, the blood-brain barrier helps to circulate the right balance of hormones, nutrients and water through the brain. It works exceptionally well – compared to the rest of the body, infections of the brain are incredibly rare. 

But while this barrier keeps our brains safe from toxins, it also poses a significant problem for modern medicine, as most drug treatments do not cross the barrier especially well. Overall, drug development for brain diseases has the poorest success rates compared to other therapeutic areas.

This means that a lot of neurological conditions, such as multiple sclerosis, Alzheimer’s disease or Parkinson’s, aren’t curable. Treatment can alleviate or lessen the severity of some symptoms, but ultimately, they become something patients have to learn to live with. 

However, researchers are becoming better and better at finding ways around the blood-brain barrier. From revolutionised drug delivery approaches to focused ultrasound, scientific research is allowing medicine to inch toward more sophisticated treatments for neurological diseases. 

Here are some of the latest projects.

Biopharmaceuticals and macromolecular drugs are becoming increasingly popular for treating previously untreatable diseases, but due to their high molecular weight they are unable to penetrate the blood-brain barrier on their own. However, a technology which could essentially ‘trick’ the brain into letting them in could be just the trick.

A team of researchers at Kumamoto University in Japan have developed a cyclic peptide, a chain of circularly bonded amino acids, that enhances penetration of the blood-brain barrier. By attaching the cyclic peptide to the surface of nanoparticles, the development of new drug nanocarriers for drug delivery to the brain could become possible.

To create their nanocarriers, the researchers turned to a family of viruses called phages, which infect and replicate within bacteria. They surveyed a phage library listing viruses with cyclic peptides able to penetrate human blood-brain barrier model cells and analysed their sequences. The rough size of a phage is 1,000 nanometres, larger than macromolecular drugs, but the scientists expected that those with cyclic peptides, which could penetrate the barrier, should be able to help enhance drug penetration too.

Over the course of their research, two new cyclic peptides, which could potentially help drugs through the blood-brain barrier, were unearthed. The M13 phage, which is larger than both macromolecular drugs and nanoparticles, was able to serve as a model macromolecule. It exhibited improved permeation across human, monkey and rat blood-brain barrier co-culture models, and could be found in the brain of a mouse within an hour of intravenous injection. 

They were also able to modify tiny vesicles called liposomes by adding the cyclic peptide to their surfaces, creating 150 nanometre artificial nanoparticles. When injected intravenously into mice, these liposomes were found within their brains 60 minutes later, showing that the new cyclic peptide facilitates the penetration of the phage and liposome nanoparticles through the blood-brain barrier.

University of Manchester researchers have also been studying the use of liposomes to bypass the blood-brain barrier. Just 100 nanometres in diameter, their research has revealed that liposomes can pass through damaged parts of the barrier following a stroke, which could offer a way to get drugs to the lesions to stop further damage.

The researchers injected fluorescent liposomes into mice, and then temporarily cut-off blood flow through a major cerebral artery to mimic the effects of a stroke. The injections were administered 30 minutes, four hours, 24 hours and 48 hours from the initial circulatory cut-off, to study the early and late effects of the stroke on the passage of liposomes.

Using in-vivo imaging and histological analysis, the researchers were able to see that selective accumulation of liposomes occurred in the damaged area of the brain where the blood-brain barrier broke down. The breakdown itself was seen to occur in two phases, with enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. 

The liposomes were able to accumulate within the affected area for several days and enhanced the neuronal repair process. Glial cells within the area blood flow was restricted were also seen to selectively take up more liposomes two to three days after the stroke.

Biopharmaceutical company Denali Therapeutics is working on a broad portfolio of products engineered to cross the blood-brain barrier and treat neurodegenerative diseases. In May 2020, it published two papers describing its Transport Vehicle (TV) technology, which was able to successfully deliver therapeutic proteins to the brain at sufficient levels for robust effects, demonstrating the normalisation of disease biomarkers in a Hunter syndrome model.

The TV technology is designed to effectively deliver large therapeutic molecules like antibodies, enzymes, proteins and oligonucleotides across the blood-brain barrier after IV administration. It is based on Fc fragments, based on the tail region of an antibody, that bind to the barrier’s transport receptors and are delivered into the brain. Animal models have seen antibodies and enzymes engineered with TV technology demonstrate over 20-times greater brain exposure than similar antibodies and enzymes without the technology. 

The drug Elaprase has been approved to treat Hunter syndrome since 2006, but, has only been able to treat bodily symptoms and not the progressive cognitive design seen in patients with the disease. 

Denali is now planning to carry out a human clinical trial to see if its TV technology can help Hunter syndrome treatments transcend the blood-brain barrier, and if so whether this will help to stop the cognitive symptoms.

Several teams of researchers around the world are using focused ultrasound to defy the blood-brain barrier, so that clinicians can deliver potential treatments directly to the brain to treat neurological diseases. The approach is designed to breach the barrier where and when needed, delivering drugs in a precise fashion.

Focusing ultrasound waves directly into the brain allows the tissue to be manipulated without ever having to make a cut. The procedure is performed under magnetic resonance imaging (MRI), meaning clinicians can watch what is happening inside the real brain as procedures are performed. 

A pilot study using this technique on four patients with amyotrophic lateral sclerosis (ALS) at Sunnybrook Research Instituted in Toronto has now demonstrated how drug molecules that are ordinarily unable to enter the brain were able to do so when focused ultrasound was used to temporarily disrupt the blood-brain barrier. No new treatments were trialled, as the study aimed to test the safety and effectiveness of the technique.

The MRI-guided focused ultrasound used microbubbles, small gas bubbles around the size of a red blood cell coated with a lipid shell, to act as a drug delivery platform. Microbubbles can be safely injected intravenously, and once they reach the blood-brain barrier the focused ultrasound makes the bubbles expand and contract within the blood vessels. 

This makes them temporarily more permeable, allowing drug molecules in the blood to pass into brain tissue. The blood-brain barrier closed within 24 hours and the patients reported no serious adverse side effected beyond headaches and mild pain.