Battle of the “City Wall”: Defending and Breaking the Blood-Brain Barrier

Produced by: Science Popularization China

Produced by: Li Juan

Producer: China Science Expo

The brain is arguably the most important organ in our body. Our ability to think, learn, communicate, move, solve problems, and make decisions all rely on this physiological foundation. After years of evolution, the brain has built a powerful defense system to protect itself.

The first layer of defense "armor" is the skull, followed by the meninges covering the brain, and then the cerebrospinal fluid with a buffering effect. Another important "guard" should not be ignored, which is the blood-brain barrier (BBB) ​​to be discussed in this article.

The blood-brain barrier is a "wall" between the bloodstream and brain cells, which is crucial to maintaining brain homeostasis. It allows only a small number of substances to pass through the blood into the brain tissue, such as water, oxygen and small fat-soluble substances, while preventing toxins, pathogens and other potentially dangerous substances from entering.

But at the same time, it is difficult for drugs to treat brain diseases to overcome this barrier and work. Researchers are trying a variety of strategies to overcome the difficulty in treating this neurological disease.

The “impenetrable” blood-brain barrier

As one of the "walls" defending the brain, the blood-brain barrier must have its "extraordinary features", which is first reflected in the structure of vascular tissue.

Unlike the peripheral blood vessels of the body, the endothelial cells in the blood-brain barrier have a special structure - tight junctions: various molecules "thread the needle" inside and outside the adjacent cell membranes, making the endothelial cells "airtight". In contrast, the endothelial cells in other parts of the body have small gaps that allow small blood-borne substances to pass through and enter the surrounding tissues (Figure 1).

Figure 1 Comparison of the structure of microvessels in the blood-brain barrier and peripheral blood vessels

(Image source: Reference 2)

In addition to endothelial cells, the function of the blood-brain barrier also depends on astrocytes and pericytes (Figure 2).

Figure 2 Brain microvascular structure

(Image source: Reference 2)

Among them, the foot processes of astrocytes account for nearly 99% of the luminal surface area of ​​brain capillaries and extend into the vessel wall. Pericytes are embedded in the vascular basement membrane and have physical connections with endothelial cells. Pericytes help maintain and stabilize the monolayer of endothelial cells in the brain and are essential for the development of tight junctions.

The interactions between these three types of cells make the blood-brain barrier a dynamic interface that regulates brain homeostasis, protects the central nervous system, and responds to different physiological and pathological states.

If the blood-brain barrier is dysfunctional, it may cause edema, signal changes, ion homeostasis disruption and immune extravasation, which in turn leads to neuronal dysfunction and ultimately neuronal cell degeneration. Diseases such as epilepsy, ischemic stroke, multiple sclerosis, traumatic brain injury and Alzheimer's disease are all characterized by damage to the blood-brain barrier. It can be seen that the role of the blood-brain barrier is extremely important.

If you continue to protect your "treasure" like this, we won't be able to protect it!

Although the blood-brain barrier can protect the brain very well, in the treatment of central nervous system diseases, drugs must cross the blood-brain barrier and be delivered to the brain parenchyma, which is the basis for maximizing the efficacy of the drugs.

In 2019, the first biologic to cross the blood-brain barrier, Zolgensma, was approved by the FDA. This is a gene therapy based on adeno-associated virus AAV9 for the treatment of infantile spinal muscular atrophy (SMA)-1. Through intravenous administration, Zolgensma delivers the functional SMN1 gene to the patient, promoting the expression of SMN protein, thereby restoring the patient's damaged motor neurons.

However, aside from this type of gene therapy, there have been few success stories in the field of drug trials for neurological diseases, with recent reports suggesting that less than 10% of therapeutic agents for neurological diseases enter clinical trials due to poor brain penetration.

Why is the blood-brain barrier so difficult to break through?

This is because the "iron wall" it constructs only allows lipophilic and low molecular weight (less than 400-500Da) molecules to enter the brain from the bloodstream through the transcellular pathway. In this case, about 98% of small molecule drugs and almost 100% of large molecule biological drugs (such as monoclonal antibodies, antisense oligonucleotides or viral vectors) cannot pass through the blood-brain barrier.

Earlier, natalizumab was approved by the FDA for the treatment of multiple sclerosis, but this monoclonal antibody also cannot cross the blood-brain barrier and works by blocking the transport of lymphocytes across the brain endothelial wall. In 2009, the FDA approved bevacizumab for adult patients with recurrent glioblastoma, but this monoclonal antibody cannot cross the intact blood-brain barrier to work.

Although the biopharmaceutical industry has been developing rapidly in recent years, there are very few FDA-approved biologics for the treatment of serious age-related brain diseases (such as Alzheimer's disease and Parkinson's disease).

In the past 25 years, many biological agents entering clinical trials lacked blood-brain barrier delivery technology and could only implement "blood-brain barrier avoidance strategies" that destroyed the blood-brain barrier or injected the drugs into the brain or cerebrospinal fluid. The results of their trials were usually ineffective, and except for very few cases, most clinical trials predictably failed.

Scientists have a hard time hiding the secrets of the blood-brain barrier

Some scholars have emphasized that the research and development of brain drugs should advance in two aspects in parallel. One is the research and development of brain drugs, and the other is the research and development of drug delivery technology that can cross the blood-brain barrier, especially technology based on the blood-brain barrier's own transport mechanism.

At present, brain drug delivery strategies can be roughly divided into invasive techniques and non-invasive techniques (Figure 5).

Fig. 5 Brain drug delivery strategies.

(Image source: Reference 3)

Invasive techniques include transient disruption of the blood-brain barrier using noxious drugs, hypertonic solutions, ultrasound or electroporation, intracerebroventricular or intrathecal infusions, etc.

Non-invasive technologies include the development of new drugs based on biological mechanisms (such as carrier- or receptor-mediated transport pathways), the development of nanoparticle systems, the application of focused ultrasound, and the use of intranasal brain drug delivery.

Compared with invasive technologies, non-invasive technologies are easier to be accepted and promoted. Among them, the research and development of technologies based on the biological transport mechanism of the blood-brain barrier itself is the top priority.

The figure below (Figure 6) lists various transport mechanisms across the blood-brain barrier, such as transcytosis or cell migration. Among them, transcytosis is the process of transporting "cargo" between cells by forming vesicles. In simple terms, drugs can cross the blood-brain barrier in the following ways:

The drug is transported to the brain via adsorption-mediated transcytosis, forming vesicles;

Through carrier-bound transcytosis, drug molecules are bound to carriers and then cross the barrier;

Through receptor-mediated transcytosis, drug protein molecules, antibodies or peptides can bind to receptors, triggering endocytosis to form vesicles for delivery to the brain - this is also the most widely studied route for brain delivery of therapeutic agents;

Through the mechanism of cell migration, monocytes or macrophages can transcytose or pass through the intercellular space to reach the brain, and then secrete or release the protein or virus-like particle drugs therein.

Figure 6 Biological transport mechanism across the blood-brain barrier

(Image source: Reference 3)

At present, scientists still need to do more work to accurately understand the biological mechanisms of the blood-brain barrier, so as to assist in the discovery of therapeutic targets for neurological diseases and determine therapeutic strategies for drug delivery.

With the rapid development of molecular techniques, imaging modalities and nanotechnology, it is believed that the knowledge network of various disciplines including medicine, chemistry, bioengineering and electronics will enable scientists to overcome the challenges posed by the blood-brain barrier in the treatment of neurological diseases.

(Note: The pictures in this article are translated into Chinese based on the original pictures in the references marked.)

References:

[1] Kadry, H., Noorani, B. & Cucullo, L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020 17, 69.

[2] Profaci CP, Munji RN, Pulido RS, Daneman R. The blood-brain barrier in health and disease: Important unanswered questions. J Exp Med. 2020. 217(4):e20190062.

[3] Terstappen GC, Meyer AH, Bell RD, Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov. 2021. 20(5):362-383.

[4] Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev. 2019. 99:21-78.

[5] Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci. 2020. 11:373.

[6] Terstappen, GC, Meyer, AH, Bell, RD et al. Strategies for delivering therapeutics across the blood–brain barrier. Nat Rev Drug Discov 2021 20, 362-383.

(Note: Latin text should be italicized.)