Enhancement of drug delivery across the blood-brain barrier for the treatment of brain diseases
Background
The blood-brain barrier (BBB) is a critical structure that protects the brain and central nervous system (CNS) by preventing most substances from crossing into these areas from the bloodstream. This protective mechanism poses a significant challenge in delivering therapeutic agents for treating brain and CNS diseases, such as brain cancer, neurologic disorders, psychological disorders, cerebrovascular disorders, brain trauma, and brain infections. According to recent estimates, millions of individuals globally suffer from these conditions, with conditions like Alzheimer's disease and Parkinson's disease affecting more than 50 million people worldwide. The current market for treatments is robust, with billions of dollars spent annually on pharmaceutical and biotechnological solutions. However, treatments are often limited to symptomatic relief and are hindered by the difficulties of delivering drugs effectively across the BBB. The current standard of care generally involves systemic administration of pharmaceuticals, which can lead to suboptimal efficacy due to limited penetration. Thus, there remains a substantial unmet need for technologies that enhance drug delivery across the BBB.
Technology Overview
The lab of Dr. Marsha Moses has developed a technology around the delivery of Rab7 GTPase (Rab7) inhibitors as a promising advancement in enhancing the permeability of the BBB. This technology leverages extracellular vesicles (EVs), such as exosomes, to co-deliver therapeutic agents and Rab7 inhibitors, thereby facilitating efficient transport of drugs across the BBB. Rab7 inhibitors reduce the expression of Rab7 in brain endothelial cells, a key factor in decreasing BBB permeability. Preliminary proof-of-concept studies demonstrate a significant increase in the delivery efficacy of drugs targeting brain diseases when used in conjunction with Rab7 inhibitors. This approach holds substantial potential for improving the delivery of anti-cancer drugs, neurologic disorder therapeutics, psychiatric medications, and other agents directly into the brain.
Applications
Development of therapeutics and diagnostics for a variety of brain diseases:
- Oncological pathologies (e.g., primary and metastatic brain cancer)
- Neurodegenerative and neurodevelopmental pathologies (e.g., autism, Alzheimer’s, Parkinson’s)
- Vascular disorders (e.g., cerebrovascular accidents (stroke), trauma- and infection-related diseases of the brain)
- Psychological disorders (e.g., PTSD, depressive disorder, bipolar disorder, obsessive-compulsive disorder, schizophrenia, etc.)
Advantages
- This method delivers the therapeutics with increased efficiency without the risk of transiently opening the BBB.
- The identification and target of pre-metastatic niche in the brain allows for early intervention in patients prone to brain metastasis.
Publications
- Morad G, Daisy CC, Otu HH, Libermann TA, Simon T. Dillon ST, Moses MA. Cdc42-dependent transfer of mir301 from breast cancer-derived extracellular vesicles regulates the matrix modulating ability of astrocytes at the blood–brain barrier. International Journal of Molecular Sciences 2020; May 28; 21(11):3851.PMID: 32481745.
- Morad G, Carmen CV, Hagedorn EJ, Perlin JR, Zon LI, Mustafaoglu M. Park T-E, Ingber DI, Daisy CC, Moses MA. Tumor-derived extracellular vesicles breach the intact blood-brain barrier via transcytosis. 2019, ACS Nano, 2019; September 10, 13(12):13853-13865, PMID:31479239 (Selected for Cover Feature).
- Morad G, Moses MA. Brainwashed by extracellular vesicles: The role of extracellular vesicles in primary and metastatic brain tumor microenvironment. Journal of Extracellular Vesicles, 2019; 8(1):1627164 PMID: 31275532.
