Scientists have finally unlocked the brain’s powerful barrier to treat neurological diseases

Woman using digital 3D projection 3D rendering of a human brain

NEW YORK – There is a protective wall that prevents harmful substances from entering the brain. Unfortunately, this also prevents life-saving medications from reaching their destination. This is a double edged sword which is blood-brain barrier. However, there may finally be a way to get essential drugs through these defenses.

For decades, crossing the blood-brain barrier has been a challenge faced by researchers trying to treat brain diseases such as Alzheimer’s disease and ALS. Now, scientists at Mount Sinai have discovered a revolutionary technique that removes the barrier and allows drugs to come into contact with your brain tissue.

In a study published in the journal Natural biotechnologyResearchers have developed a new “blood-brain barrier-crossing conjugate” (BCC) that can deliver therapeutic molecules directly to the brain through a simple intravenous injection.

“Our platform has the potential to solve one of the biggest obstacles in brain research,” Dr. Eric J. Nestler, co-corresponding author and senior author of the study, said in a press release. “This development has the potential to improve treatments for a wide range of brain diseases.”

Brain-barrier conjugates provide systemic delivery of large therapeutic molecules to the brain. — Brain-barrier conjugates enable systemic delivery of large therapeutic molecules to the brain. (Photo: Laboratory of Yizhou Dong, Ph.D., at Mount Icahn-Sinai)

The breakthrough occurred through a specialized biological process called γ-secretase-mediated transcytosis. By attaching genetic tools to a compound called BCC10, the researchers successfully delivered therapeutic molecules to the brains of mice. In experiments on mice with ALS, they sharply reduced the level of disease-causing genes, demonstrating the potential effectiveness of the method.

Importantly, the treatment showed minimal side effects. The mice tolerated the injection well, with virtually no damage to major organs at the doses tested. The researchers even tested their approach using human brain tissue samples in a laboratory setting.

“Our BCC platform overcomes this barrier by allowing biomacromolecules, including oligonucleotides, to safely and effectively reach the CNS,” emphasizes Dr. Yizhou Dong, another senior author of the study.

Despite the promising results, the research is still in its early stages. The team plans further studies in larger animal models to test and develop the therapeutic potential of the platform. However, this breakthrough offers hope to millions of people suffering from neurological diseases that are notoriously difficult to treat. The next frontier of brain medicine may have just found its key.

Summary of the article

Methodology

This study focused on developing and testing a novel delivery system for biomacromolecules such as oligonucleotides across the blood-brain barrier (BBB). The researchers synthesized a set of blood-brain barrier-crossing conjugates (BCCs), which are compounds designed to bind and cross the BBB using specific pathways. These conjugates were administered to mice and their ability to cross the BBB and reach the central nervous system was measured.

The researchers used fluorescent markers to track molecules in the brain and used methods such as quantitative polymerase chain reaction (qPCR) to measure gene silencing activity. Additional in vitro experiments used human brain cell models to reproduce BBB crossing under controlled conditions.

Key Results

The study found that one particular conjugate, BCC10, showed remarkable efficacy in crossing the BBB. When administered to mice, BCC10 delivered biomacromolecules at levels hundreds of times higher than previous methods. The results confirmed that the conjugate works through the use of γ-secretase, a protein that facilitates the transport of molecules across the barrier.

In addition, BCC10 was able to efficiently deliver genetic material by silencing target genes in both mouse brains and human brain tissue samples. The conjugates showed minimal toxicity in critical organs and no significant inflammatory responses were observed, making this approach a promising advance in the treatment of central nervous system diseases.

Study Restrictions

The study primarily used mice, whose physiological differences from humans may affect the effectiveness of the conjugates. Ex vivo experiments on human brain tissue provide some information, but do not fully replicate in vivo human conditions. Additionally, long-term safety studies have not been conducted, so the potential chronic effects of the conjugates remain unknown. Another limitation is that the study focused on a specific delivery mechanism (γ-secretase-mediated transcytosis), which may not apply to all therapeutic molecules.

Discussion and conclusions

This study demonstrates an innovative approach to overcome the BBB, a major obstacle in developing treatments for neurological diseases. The ability of the BCC10 conjugate to cross the BBB and deliver genetic material opens up new opportunities for the treatment of diseases such as Alzheimer’s disease, ALS and brain tumors. The findings also highlight the role of γ-secretase in mediating molecular transport across the BBB, suggesting a new target for drug delivery strategies. Future work will need to address the scalability of this method and test its effectiveness in different populations and disease models.

Funding and Disclosure

The study was conducted primarily with support from the Icahn School of Medicine at Mount Sinai. Dr. Yizhou Dong, the senior author, disclosed potential conflicts of interest, including serving as a scientific consultant for several biotechnology companies and being a co-founder of Immunanoengineering Therapeutics, in which he holds shares. Other researchers involved in the study declared no competing interests.