The blood-brain barrier: a notorious therapeutic target
- academicmemories
- May 24
- 5 min read
Ean L. Small
Introduction
Neurological diseases, including Parkinson’s and Alzheimer's Disease, are ever-increasing with global diagnosis expected to rise 30% by 2030 [1]. The ongoing exhaustive research efforts on central nervous system (CNS) disorders have yielded few effective treatments that cure or reverse disease progression (i.e. its pathogenesis). Despite tremendous recent progress, this failure is primarily due to the brain’s protective mechanism, the blood-brain barrier (BBB), which readily rejects beneficial drugs. In fact, the BBB limits drug uptake such that less than 0.1% of a therapeutic dose enters the brain [2]. This makes the BBB an obstacle that researchers must overcome to enhance drug delivery and ultimately cure neurodegenerative diseases.
Composition of the BBB
The BBB is a regulatory system that protects the brain from foreign toxins and pathogens circulating in the blood, while simultaneously allowing essential nutrients, such as iron, sugars, and other complex proteins, into the brain [3]. Without this barrier, we would be vulnerable to frequent brain infections, limiting health and longevity. The BBB is composed of four main components, which are described below:
Endothelial cells: The core contributor to the lining of cerebral blood vessels, and are responsible for interacting with different cell types in the CNS [4]. Endothelial cells are the first line of defense against toxins in the bloodstream that are trying to enter the brain. Additionally, these cells have increased mitochondrial levels, meaning they have a greater energy bandwidth dedicated to transporting beneficial molecules across the BBB [3].
Astrocytes or astroglia: Primarily responsible for cell maintenance, interaction, and mediation of cell-to-cell communication [3]. Astrocytes play a crucial role in maintaining the seamless entry of key nutrients into the brain. Interestingly, in some invertebrate species that lack all the components of our BBB, astrocytes are the primary gatekeepers between toxins and the CNS [3].
Pericytes: Essential for the integrity of the BBB by creating tight junctions. These junctions, also known as small pores, between cells prevent large proteins that could disrupt proper brain function from crossing into the CNS. Without pericytes, the BBB would be incredibly permeable, allowing entry to nearly all pathogens in the blood.
Microglia: The medical staff for cells that compose the BBB. Microglia regulate neuronal division and provide nutritional support to neighboring cells, underscoring their crucial role in maintaining the integrity of the BBB [4].
These four cell types work in unison to defend the brain against potential intruders. While we appreciate the BBB for its role in preserving brain health, it also poses a significant challenge to the treatment of neurological diseases that reside in the brain. We will next cover the mechanisms by which key nutrients cross the BBB and how researchers can utilize these transport systems to develop novel drug therapies.
Crossing the BBB
There are various methods that the cells listed above, primarily endothelial cells, employ to facilitate the passage of nutrients into the brain. Among these are passive diffusion and physical channels through which molecules can pass. Passive diffusion is the process by which proteins can float through cell membranes, much like ghosts can move through closed doors [4]. However, this passive process is limited to small proteins, molecules that are typically not included in drugs [3,4]. Physical channels, on the other hand, allow for the passage of larger proteins through a process called receptor-mediated transcytosis (RMT), where receptors on the cell surface transport nutrients, such as iron, across the BBB (Figure 1) [4]. Transcytosis can be thought of as a concierge service that shuttles nutrients through the body's barriers, making screening unnecessary. Furthermore, the channels involved in RMT are distinct proteins that may be expressed solely on brain endothelial cells, making them an enticing target for therapeutics.
Current and novel therapeutic strategies to circumvent the BBB
Previous attempts to bypass the BBB involve highly invasive drug administration. Among the most popular include intrathecal injections, where medical practitioners administer drugs at the base of the spinal cord, injecting into the cerebrospinal fluid with the hopes that the drugs make their way into the brain via the brain stem [5]. Other invasive methods used to treat neurological diseases include convection-enhanced drug delivery (injection directly into the brain), intracranial implantation, and deep-brain stimulation [4]. As such, researchers have been impatient to develop new methods of delivering drugs to the brain safely and effectively.
Recently, scientists have engineered protein shuttles that exploit RMT to transport drugs across the BBB. These proteins, often in the form of antibodies or enzymes, target receptors on brain endothelial cells, induce the internalization of those receptors, and dissociate once inside the brain to bind their specific target (Figure 1). For instance, Denali Therapeutics currently has multiple enzyme and antibody shuttle molecules in clinical trials that utilize RMT to enhance drug delivery in the brain. These drugs are used to treat Hunter Syndrome, Frontotemporal Dementia-granulin, and Hurler Syndrome [7,8,9].
Conclusions
Neurological diseases are notoriously difficult to treat, and in the case of degenerative CNS disorders, there are no current medications that cure or reverse pathogenesis. This poses a great challenge for the 3.4 billion people worldwide who are suffering from Alzheimer’s, Parkinson’s, and Multiple Sclerosis, to name a few [9]. The use of novel shuttle molecules represents a significant advancement in research aimed at crossing the BBB. Furthermore, these engineered drugs could resolve symptoms and disease progression for over 40% of the global population [9]. This research not only contributes directly to the development of drugs for CNS diseases, but it also highlights the significance of harnessing natural processes in the human body for therapeutic purposes. This article serves as a reminder that every research effort, whether large or small, plays a pivotal role in answering the underlying biological question. In the future, it will be exciting to see these shuttle drugs advance in the clinic and observe the continual progress of research in this field.
Literature Cited
[1] Chen, R.C. et al. Prevalence, incidence, and mortality of PD. Neurology. https://doi.org/10.1212/WNL.57.9.1679
[2] Bajracharya R. et al. Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain. Pharmaceutics. https://doi:10.3390/pharmaceutics13122014
[3] Wu, D., Chen, Q., Chen, X. et al. The blood–brain barrier: Structure, regulation and drug delivery. Sig Transduct Target Ther. https://doi.org/10.1038/s41392-023-01481-w
[4] https://www.bblsa.com/analyst-reports/2024/11/12/frontiers-in-cns-therapeutic-development- breaching-the-blood-brain-barrier
[5] Fowler, M.J. Intrathecal drug delivery in the era of nanomedicine. Advanced Drug Delivery Reviews. https://doi.org/10.1016/j.addr.2020.02.006
[6] Arguello A, Meisner R, Thomsen ER, et al. Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome. JCI Insight. https://doi:10.1172/jci.insight.145445
[8] https://www.globenewswire.com/news-release/2025/01/13/3008476/0/en/Denali-Therapeutics- Announces-Key-Anticipated-2025-Milestones-and-Priorities-to-Further-Advance-Its-Therapeutics-Portfolio-for-Neurodegeneration-and-Lysosomal-Storage-Diseases.html
[9] Steinmetz, J.D. et al. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology. https://doi.org/10.1016/S1474-4422(24)00038-3
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