New Platform Facilitates Drug Delivery Across the Blood-Brain Barrier
Mount Sinai researchers unveil a safe platform to deliver therapies across the blood-brain barrier.
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Researchers at the Icahn School of Medicine at Mount Sinai have developed a method to deliver therapeutic molecules into the brain, a significant challenge due to the protective nature of the blood-brain barrier (BBB). The technique, described in Nature Biotechnology, was tested in mouse models and human brain tissue, opening potential pathways for treating diseases such as ALS, Alzheimer’s and addiction.
Blood-brain barrier (BBB)
A semi-permeable network of cells and blood vessels that protects the brain from harmful substances in the bloodstream while restricting the passage of therapeutic agents.
The BCC platform: bypassing the blood-brain barrier
The BBB, while critical for protecting the brain from toxins, also impedes large biomolecules like proteins and oligonucleotides from entering the central nervous system (CNS). The newly developed blood-brain barrier-crossing conjugate (BCC) platform employs γ-secretase-mediated transcytosis, a biological process that allows these molecules to cross the BBB via intravenous injection.
“The blood-brain barrier is an essential defense mechanism, but it also presents a significant challenge for delivering drugs to the brain,”
Dr. Yizhou Dong
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Subscribe for FREEIn animal studies, the researchers demonstrated that a compound called BCC10 linked to antisense oligonucleotides effectively reduced the expression of disease-related genes. For instance, in a mouse model of ALS, BCC10 silenced the Sod1 gene, known for its role in the disease. Similarly, targeting the Mapt gene in Alzheimer’s models reduced tau protein levels, a major therapeutic goal in neurodegenerative diseases.
Antisense oligonucleotides
Short, synthetic strands of DNA or RNA that bind to specific genetic sequences to block gene expression or modify RNA splicing.
γ-secretase-mediated transcytosis
A cellular mechanism that facilitates the transport of molecules across barriers, such as the BBB, by engaging the enzyme γ-secretase to mediate the process.
Translational potential and safety profile
The platform not only achieved gene silencing in vivo but also demonstrated effectiveness in human brain tissue samples in the lab. Notably, the approach appeared well-tolerated in mice, with minimal adverse effects on major organs at tested doses. This safety profile underscores its promise for further development.
Future directions for BCC technology
Although progress in overcoming the BBB has advanced, researchers emphasize the need for systemic drug delivery technologies that can safely and efficiently target the CNS. Future research will focus on validating this approach in larger animal models, a key step toward its potential clinical application.
Reference: Wang C, Wang S, Xue Y, et al. Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system. Nat Biotechnol. 2024. doi: 10.1038/s41587-024-02487-7
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