The Journey Across the Blood-Brain Barrier

The blood–brain barrier shields the central nervous system from harm, but its formidable defenses can also block many promising therapeutics.

Blue outline of a human brain on a black background.

The human brain is a fortress. Enclosed within a network of tightly packed endothelial cells, the blood–brain barrier (BBB) serves as a vigilant gatekeeper, admitting only what the brain deems essential—oxygen, glucose, select amino acids—while denying passage to most other circulating molecules. This microscopic boundary shields the central nervous system (CNS) from toxins, pathogens, and fluctuations in the body’s internal chemistry, preserving the brain’s delicate equilibrium. But this same barrier—so vital to survival—poses one of medicine’s most formidable challenges when it comes to figuring out how to deliver drugs across it.

For decades, scientists have sought ways to sneak therapeutics past the BBB’s defenses. Large molecules such as proteins, antibodies, and viral vectors are generally too bulky to cross in clinically meaningful quantities. Even small molecules, once thought to be the answer, rarely traverse on their own. A fraction of a drug may breach the barrier, but reaching therapeutic concentrations may require escalating the systemic dose to toxic levels. The result is a frustrating paradox: treatments that work in theory falter in practice because they cannot reach their target.

This impasse has humbled even the most promising programs. Roche’s gantenerumab, a monoclonal antibody designed to clear amyloid plaques from the brains of Alzheimer’s patients, once carried great expectations.1 Yet despite lowering amyloid plaque burden, the drug was not associated with slower clinical decline. Likewise, UCB’s minzasolmin, an oral small molecule intended to correct the misfolding of alpha-synuclein in Parkinson’s disease, was discontinued after disappointing clinical results.2 These setbacks underscore the complexity of CNS disorders. Still, progress continues, fueled by new technologies and strategies.

Strategies for Breaching the BBB to Deliver Drugs

Researchers are exploring specialized formulation and delivery strategies tailored to the brain’s unique physiology. Invasive methods, such as direct administration into the intrathecal space, can bypass the BBB entirely, ensuring high drug concentrations at the target site. However, these approaches are complex, costly, and carry risks associated with surgery and infection.

Non-invasive strategies aim to finesse the barrier rather than circumvent it. Some involve chemical modification, tweaking a molecule’s structure or lipophilicity to improve its ability to pass through the BBB’s tight junctions. Others leverage intranasal administration, which offers rapid absorption through the olfactory pathways, though variability among patients—due to anatomical differences, congestion, or nasal drainage—limits its reliability. Another line of research focuses on temporarily altering the BBB using ultrasound, electroacupuncture, or hyperosmotic agents such as mannitol, allowing therapeutics to enter during short, controlled windows of increased permeability.

A particularly promising class of innovations involves molecular piggybacking, in which drugs are conjugated to ligands like transferrin or low-density lipoprotein receptor-related protein 1 (LRP1) that bind to receptors on endothelial cells, effectively hitching a ride across the barrier.

Yet perhaps the most dynamic area of progress lies in delivery systems, including liposomes, extracellular vesicles, nanoparticles, and viral vectors, that encapsulate and ferry drugs to the brain. Among these, adenoassociated viruses (AAVs) remain a cornerstone, and recent efforts in engineering the protein shell of the virus have yielded variants capable of targeting neural tissue with increasing precision.

New Approaches, Renewed Hope

These collective efforts mark a turning point for neurotherapeutics. Although there have been setbacks over the years, each failure refines the field’s understanding of how to navigate the brain’s defenses. Roche, for instance, has not abandoned gantenerumab entirely. The company has developed trontinemab, a version of gantenerumab fused to Roche’s proprietary Brainshuttle domain (an innovation designed to ferry large molecules across the BBB more efficiently).

As another example, uniQure’s one-time gene therapy AMT-130, delivered via an adeno-associated virus (AAV) vector directly into the brain, recently demonstrated a 75% reduction in disease progression over three years in patients with Huntington’s disease.

The brain may still be a fortress, but science is learning how to open its gates. As technologies mature and understanding deepens, the prospect of effectively delivering drugs to the brain no longer seems so remote. What was once an impenetrable barrier may soon become a bridge to a new generation of treatments for some of medicine’s most intractable neurological disorders.

References

1. Bateman RJ, Smith J, Donohue MC, et al. Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease. N Engl J Med. 2023;389(20):1862-1876.

2. The Michael J. Fox Foundation for Parkinson’s Research. “News in Context: Mixed Results from Two Experimental Drugs Targeting Alpha-Synuclein.” https://www.michaeljfox.org/news/news-context-mixed-results-two-experimental-drugs-targeting-alpha-synuclein.

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