May 15, 2007
La Jolla, CA – Researchers at the Salk Institute for Biological Studies have overcome a long-standing problem in biology by equipping a protein with a small homing device, allowing it to slip behind the blood-brain barrier. Circumventing this barrier – specifically designed to keep substances out of the brain – is a crucial step for the delivery of drugs to the central nervous system (CNS).
“The failure rate to deliver drugs to CNS is unfortunately very high, so any new methods of drug, protein and gene delivery should be welcome,” says Inder Verma, Ph.D., a professor in the Laboratory of Genetics and senior author of the study published in the Proceedings of the National Academy of Sciences.
Using a small fragment of apolipoprotein B as a guide, Brian Spencer, a postdoctoral fellow in the Verma lab and the study’s lead author, successfully shepherded the enzyme glucocerebrosidase into the brains of adult mice. In humans, a lack of this enzyme underlies Gaucher’s disease, an inherited and often fatal disorder caused by the toxic build up of glucocerebroside. While enzyme replacement therapy can correct the deficiency in peripheral tissues, researchers have been unable to channel the enzyme across the so-called blood-brain barrier to prevent the accumulation of glucocerebroside in the brain, which results in neuronal degeneration.
Unlike peripheral capillaries, which allow the relatively free exchange of substances with the surrounding tissue, the capillaries in the brain are tightly packed with endothelial cells. This physical barrier severely limits access to brain tissue, and only lets a select few chemicals slip in. The blood-brain barrier not only protects the brain from pathogens and potentially harmful substances, it also makes neural disorders such Alzheimer’s and Gaucher’s disease extremely difficult to treat.
“The only way we could deliver therapeutic proteins or drugs to the brain was via direct injection where you target a specific brain area or by chemically disrupting the blood-brain barrier, which permits proteins in the blood to enter the brain indiscriminately,” says Spencer, now a project program scientist in the Department of Neuroscience at the University of California, San Diego.
To overcome this seemingly impenetrable barrier, the Salk researchers exploited one of the mechanisms that allow the brain to import essential nutrients and molecules such as cholesterol from the bloodstream. Low-density lipoprotein (LDL) receptors, which can be found on the surface of most cells including endothelial cells, for example, shuttle large molecules such as apolipoprotein B across the blood-brain barrier. So, the researchers attached a fragment of apolipoprotein B to glucocerebroside, hoping that it would transport the enzyme into the brain.
Next, they used gene therapy to provide a continuous supply of modified glucocerebroside to the brain. A lentiviral “gene taxi” ferried the modified gene to the animals’ liver and spleens, which started to churn out tagged glucocerebrosidase. Two weeks later, Spencer could detect the enzyme not only in peripheral tissues but also in the brain.
“In our study, we used a gene therapeutic approach, but you could purify the modified protein and inject it intravenously just like it is already done for enzyme replacement therapy,” explains Spencer.
In a commentary accompanying the article, professor Vivian Teichberg , a neurobiologist at the Weizmann Institute of Science, described this technology as a breakthrough that can influence the outcome of many CNS related diseases.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.