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FOR RELEASE - Monday, May 4, 1998
MOUNT SINAI RESEARCHERS ATTAIN GLOBAL DELIVERY OF COMPACTED DNA THROUGH DISRUPTED BLOOD-BRAIN BARRIER
Successful Crossing of Blood-Brain Barrier With Gene Delivery Constructs Is First Step In Treating Diseases of Central Nervous System
Researchers at Mount Sinai School of Medicine in New York announced that they have successfully disrupted the blood-brain barrier in lab rats and generated compacted protein/DNA complexes small enough to pass through the disrupted barrier, thereby achieving global delivery of genes to the brain for the first time. The successful crossing of the barrier, which is the first step in treating diseases of the central nervous system, was announced today during a presentation at the Pediatric Academic Societies' Annual Meeting in New Orleans.
The blood-brain barrier is composed of billions of endothelial cells, which so tightly line the capillaries pumping blood to the brain that they form a virtually seamless barrier preventing a wide array of substances from reaching the brain.
Mount Sinai researchers briefly and reversibly disrupted the barrier in 17 of 28 lab rats by injecting a hyperosmolar solution (a concentrated sugar solution) in their carotid artery. Following blood-brain barrier disruption, a compacted protein/DNA package was injected into each rat's common carotid artery.
The protein/DNA packages consisted of a DNA plasmid vector expressing a reporter gene (green fluorescent protein), which was complexed and compacted with one of two DNA-compacting proteins - salmon sperm protamine and poly-L-lysine. Upon examination, the packages were determined to be smaller in diameter than the transient openings of the disrupted blood-brain barrier.
To determine if the protein/DNA packages crossed the barrier into the brain matter, the Mount Sinai scientists separated the capillary vessels from the brain of the injected rats and analyzed the brain matter for the presence of the injected DNA using the polymerase chain reaction. Upon inspection, the injected DNA was found to have successfully crossed the barrier and entered the brain matter in all 17 rats whose blood-brain barriers had been successfully disrupted.
Five other rats were similarly treated and allowed to recover from surgery. Five days later, their brains were analyzed for expression of the green fluorescent protein marker gene. The brains of these rats were found to contain numerous marker cells in diverse regions of the brain, indicating that brain cells were globally accessed by the injected DNA.
"The next frontier in the field of gene therapy is to tackle the diseases of the central nervous system," says Dr. Yiannis A. Ioannou, the lead researcher of the project and an Assistant Professor of Human Genetics, Gene Therapy and Molecular Medicine, Department of Human Genetics, Mount Sinai School of Medicine. "By successfully crossing the blood-brain barrier and utilizing global delivery of genes to the brain, we have taken a major first step in enabling potentially beneficial medications to bypass this physical barrier and reach their intended target."
Dr. Ioannou said the next step in the research process is to apply this approach to treat laboratory animals that are affected by diseases mirroring human afflictions.
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