One Shot of Gene Therapy Spreads Through Brain


By targeting a site in the brain well connected to other areas, researchers successfully delivered a beneficial gene to the entire brain - after just one injection of gene therapy. These results may have potential for gene therapy to treat a host of rare but devastating congenital human neurological disorders, such as Tay-Sachs disease.

Researchers from Children's Hospital and the University of Pennsylvania reported their findings in the September 12 issue of the Journal of Neuroscience.

"After a single injection, this technique succeeded in correcting diseased areas throughout the brain," says study leader John H. Wolfe, V.M.D., Ph.D., a neurology researcher at Children's Hospital and a professor of pathology and medical genetics at the Penn School of Veterinary Medicine. "This may represent a new strategy for treating genetic diseases of the central nervous system."

Wolfe and Penn graduate student Cassia N. Cearley performed the study in models of the neurogenetic disease mucopolysaccharidosis type VII (MPS VII). MPS VII, also called Sly syndrome, is a rare, multisystem disease causing mental retardation and death in childhood or early adulthood.

Sly syndrome is one of a class of some 60 disorders called lysosomal storage diseases that collectively cause disabilities in about one in 5,000 births. In each of these diseases, a specific gene defect disrupts the production of an enzyme that cleans up cellular waste products. Cellular debris builds up within cell storage sites called lysosomes, and the waste deposits interfere with basic cell functions.

For most lysosomal storage diseases, enzyme replacement is not very effective in treating the brain component of the disease because enzymes delivered to the circulation do not cross the blood-brain barrier very well. Therefore, treatment strategies have focused on gene therapy-delivering DNA sequences that can enter cells and produce the needed enzyme. Researchers have also sought to deliver gene therapy directly to the brain rather than to the bloodstream, but there are practical limitations to making multiple injections into a child's brain.

In the current study, Wolfe targeted a particular region of the brain called the ventral tegmental area (VTA), which has numerous connections with the rest of the brain. He used a subtype of adeno-associated virus (AAV) vector - the delivery vehicle for the gene that carries coded instructions to produce the desired enzyme.
The enzyme produced by the gene therapy approach cleaned up the storage lesions to the point that they were indistinguishable from those found in the brains of non-disease models. One advantage of lysosomal enzymes is that cells receiving the delivered gene secrete beneficial enzymes to neighboring cells, creating a "sphere of correction."

The level of correction resulting from a very small injection was "unprecedented," according to Dr. Wolfe, but he cautioned that direct human treatments might be years away. Although this approach would probably require several injections in a child's brain, the number of injections could be greatly reduced if similar strategies work in a large mammalian brain. The hope is that a few strategic injections into the right structures would help correct much larger amounts of brain and would make the surgery more feasible.

In future studies, he will investigate whether this technique is effective in larger models of disease. Such results might conceivably resemble a 2005 study in which Wolfe used gene therapy to successfully treat models of another lysosomal storage disease, called alpha- mannosidosis.

If these results can be successfully extrapolated to humans, Wolfe estimates that 2 milliliters of injected gene therapy might treat a one-year-old child using a reasonably limited number of injections. However, a great deal of work would be needed to reach that goal.

Grants from the National Institutes of Health supported this research.