Researchers at Carnegie Mellon University have created genetically engineered adult neural stem cells which can be delivered to the brain to produce and supply missing proteins. "We are particularly interested in targeting the brain because this area of the body is protected by the so-called blood-brain barrier that has been very difficult to penetrate with therapeutic enzymes that are usually injected into the patient's bloodstream," lead developer and Carnegie Mellon biomedical engineering assistant professor Stefan Zappe said. Zappe, who is working in conjunction with Dr Raymond Sekula, a neurosurgeon at Allegheny General Hospital, said he selected adult neural stem cells because they could be harvested from the patient's brain, had the potential to be multiplied outside the body, could be genetically engineered, could disperse within the brain once re-implanted, and could replace all major cell types of the brain. The one problem facing the researchers was that re-implanted stem cells produced an inflammatory response and would cause the stem cells to differentiate into mature cell types which would not be clinically effective as the cells would not disperse. To address the problem, the researchers have developed cell-instructive microcapsules that contain the genetically engineered neural stem cells. These protect the stem cells from premature differentiation. The caviar-sized microcapsules also control whether the stem cells proliferate, whether they differentiate into more specialised cells types and the extent of migration. Once the brain has healed from the initial implant of the encapsulated stem cells, the stem cells are genetically engineered to produce an enzyme that eats the microcapsule thereby freeing the stem cells which then migrate into the surrounding brain tissue where they are programmed to produce the missing protein. The idea behind the technology being developed is to give clinicians the ability to genetically engineer neural cells from the patient, re-implant them and remotely control their actions in non-invasive ways. "By using inducible gene expression, we hope to provide physicians with external control over capsule degradation and the amount of therapeutic enzyme released into the brain by engineered cells as determined by the dose of the drugs that are given to the patient in pill form," Zappe said. The team is currently looking at Hunter syndrome, where patients lack the enzyme iduronate-2-sulfatase, which helps cells break down certain waste products. One in every 130,000 boys is born with the rare but deadly genetic disorder. "Hunter syndrome is a devastating illness. Over time, toxic waste products accumulate in the cells of the body, and, although progression of the disease varies, the majority of children die in their teens. If we can reliably provide the missing enzyme iduronate-2-sulfatase to the central nervous system of these children, we may change the course of this disease," Sekula said. "Our technology and methodology also will likely have far-reaching implications for hundreds of other diseases of the central nervous system." Analysts have estimated the gene therapy market will reach more than $5bn by 2011.
