A dilemma in treating diseases of the central nervous system is that many drugs infused into the bloodstream cannot pass through a network of specialized capillaries that allows passage of only sanctioned molecules to the brain.
This protective brain fence, otherwise known as the blood-brain barrier, keeps toxins and pathogens out of the brain circulation. Having a means to circumvent it when necessary would give clinicians a major leg up in treating brain disorders.
In a study published in Proceedings of the National Academy of Sciences, postdoctoral fellow Brian Spencer and Inder Verma, professor in the Laboratory of Genetics, have developed a technique that allows the transport of proteins like glucocerebrosidase, an enzyme whose deficiency causes Gaucher's disease, as a model to create a means to get around this problem.
Gaucher's disease, an inherited and often fatal disorder, is caused by the build-up of substances called glucocerebrosides due to deficiency in the enzyme that metabolizes them, a protein known as glucocerebrosidase.
Researchers have been unable to deliver glucocerebrosidase across the blood-brain barrier to prevent glucocerebroside accumulation in the brain, which results in neuronal degeneration.
Working in the Verma laboratory, Spencer was successful in shepherding glucocerebrosidase into mouse brains by first fusing the gene encoding it to portions of another gene encoding the protein apolipoprotein B, which readily crosses the barrier.
Next, they used a gene therapy approach to express the hybrid gene in the liver. This manipulation provided a continuous supply of the glucocerebroside/apolipoprotein B fusion protein in the bloodstream.
Two weeks later, glucocerebrosidase was detectable in the brain, indicating that the apolipoprotein B part of the hybrid protein acted as a guide and dragged the unsanctioned glucocerebrosidase across the barrier and into brain cells.
Verma and Spencer's approach is a major breakthrough in the field which could potentially be developed into a method to deliver other therapeutic proteins through the capillary barrier and into the central nervous system.