C15524 Marketing Summary: Method for reversible blood-brain barrier opening using melittin and melittin variants
Inventors: Peter Charles Searson, Kalina Hristova, Raleigh Linville, Alexander Komin, Piotre Walczak
Unmet Need
The blood-brain barrier (BBB) is responsible for regulating the brain microenvironment by tightly controlling the entry of molecules and cells into the brain. This restricted access has presented challenges in the delivery of therapeutic agents to the brain. As a result, only a few central nervous system disorders are currently treatable with small-molecule drug therapy. One strategy to enable drug delivery to the brain is to induce transient opening of the blood-brain barrier. Unlike transcellular transport, blood-brain barrier opening involves reversible mechanical or chemical disruption of cell junctions to allow transient paracellular transport between endothelial cells. Transient opening allows drugs to extravasate from circulation into the brain. The current standard for delivering agents to the brain involves intra-arterial injection of the hyperosmotic agent mannitol, which transiently opens the BBB. This technique has been used for several decades in both preclinical models and in the clinic to improve delivery of therapeutics. However, difficulties in reproducibility have prevented widespread use of this method in the clinic.
Technology Overview
Johns Hopkins researchers have adopted a strategy of inducing transient opening of the blood-brain barrier using membrane active peptides (MAPs). In particular, they show that melittin, a major component of the venom of the honey bee (Apis mellifera), and its sequence variants can induce transient BBB opening and overcome the limitations of current methods used in the clinic, such as hyperosmotic treatment with mannitol. Transient opening of the BBB with melittin would enable delivery of a wide range of diagnostic and therapeutic agents and drug and gene delivery systems into the brain. Thus, this approach is highly versatile and could be used to increase brain penetration of existing FDA-approved therapeutics.
Stage of Development
Preclinical and experimental data is available for in vitro and in vivo studies where inventors have demonstrated that melittin enables reversible BBB opening and highlighting the diverse range of therapeutic compounds for which melittin can enhance drug delivery.
Publications
Linville RM, Komin A, Lan X, DeStefano JG, Chu C, Liu G, Walczak P, Hristova K, Searson PC. Reversible blood-brain barrier opening utilizing the membrane active peptide melittin in vitro and in vivo. Biomaterials. 2021 Aug;275:120942. doi: 10.1016/j.biomaterials.2021.120942. Epub 2021 Jun 10. PMID: 34147718; PMCID: PMC8330225.
