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NEW YORK — There is a protective wall that keeps harmful substances from reaching your brain. Unfortunately, it also prevents life-saving medicines from reaching their destination as well. This is the double-edged sword that is the blood-brain barrier. However, there may finally be a way of letting needed medication through these defenses.
For decades, bypassing the blood-brain barrier has been the challenge facing researchers trying to treat brain diseases like Alzheimer’s and ALS. Now, scientists at Mount Sinai have discovered a groundbreaking technique that unlocks the barrier, allowing drugs to make contact with your brain tissue.
In a study published in the journal Nature Biotechnology, researchers developed a novel “blood-brain barrier-crossing conjugate” (BCC) that can deliver therapeutic molecules directly into the brain through a simple intravenous injection.
“Our platform could potentially solve one of the biggest hurdles in brain research,” says Dr. Eric J. Nestler, a co-corresponding senior author of the study, in a media release. “This development has the potential to advance treatments for a broad range of brain diseases.”
The breakthrough comes from a specialized biological process called γ-secretase-mediated transcytosis. By attaching genetic tools to a compound called BCC10, researchers successfully delivered therapeutic molecules into mouse brains. In experiments using mice with ALS, they dramatically reduced levels of disease-causing genes, demonstrating the method’s potential effectiveness.
Crucially, the treatment showed minimal side-effects. Mice tolerated the injection well, with little to no damage to major organs at tested doses. The researchers even verified their approach using samples of human brain tissue in laboratory settings.
“Our BCC platform breaks this barrier, allowing biomacromolecules, including oligonucleotides, to reach the CNS safely and efficiently,” emphasizes Dr. Yizhou Dong, the other co-corresponding senior author of the study.
While promising, the research is still in early stages. The team plans further studies in larger animal models to validate and develop the platform’s therapeutic potential. However, this breakthrough offers hope for millions suffering from neurological conditions that have been notoriously difficult to treat. The next frontier of brain medicine might just have found its key.
Paper Summary
Methodology
This study focused on developing and testing a novel system to deliver biomacromolecules, such as oligonucleotides, across the blood-brain barrier (BBB). Researchers synthesized a set of blood-brain barrier-crossing conjugates (BCCs), which are compounds designed to bind and traverse the BBB using specific pathways. These conjugates were injected into mice, and their ability to cross the BBB and reach the central nervous system was measured.
The researchers used fluorescence markers to track the molecules in the brain and employed techniques like quantitative polymerase chain reaction (qPCR) to measure gene-silencing activity. Complementary in vitro experiments used human brain cell models to replicate BBB crossing under controlled conditions.
Key Results
The study found that one specific conjugate, BCC10, showed remarkable efficiency 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 worked by leveraging γ-secretase, a protein that facilitates molecule transport across the barrier.
Additionally, BCC10 was able to deliver genetic material effectively, silencing targeted 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 the approach a promising step forward for treating central nervous system diseases.
Study Limitations
The study primarily used mice, which have physiological differences from humans that could affect how the conjugates perform. The ex vivo experiments on human brain tissue provide some insights but do not fully replicate in vivo human conditions. Furthermore, long-term safety studies were not conducted, leaving potential chronic effects of the conjugates 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 & Takeaways
This research demonstrates a groundbreaking approach to overcoming the BBB, a major obstacle in developing treatments for neurological diseases. The BCC10 conjugate’s ability to cross the BBB and deliver genetic material opens new avenues for treating conditions like Alzheimer’s disease, ALS, and brain tumors. The findings also highlight the role of γ-secretase in enabling molecular transport across the BBB, offering a novel target for drug delivery strategies. Future work will need to address the scalability of this method and test its efficacy in diverse populations and disease models.
Funding & Disclosures
The study was primarily supported by the Icahn School of Medicine at Mount Sinai. Dr. Yizhou Dong, a senior author, disclosed potential conflicts of interest, including serving as a scientific advisor for several biotechnology companies and being a co-founder of Immunanoengineering Therapeutics, in which he holds equity. The other researchers involved in the study declared no competing interests.
