12 November 2002. By guest writer Brenda Patoine. Preliminary results of the NGF gene therapy clinical trial in early-stage AD illustrate the potential promise-and pitfalls-of gene therapy for neurodegenerative diseases.
Mark Tuszynski of the University of California, San Diego, presented early data from this first clinical use of gene therapy in humans with AD at the Neuroscience meeting last Wednesday. Alzforum covered the start of this trial (see related news story). To date, eight patients have received transplants, which are autologous grafts of skin fibroblasts transfected with the human NGF gene. Two of the eight developed serious brain hemorrhages due to movement during surgery, and one died as a result.
Surgical techniques for subsequent patients were then refined, Tuszynski said. While the procedure is not complex, he noted that it is technically challenging due to the careful planning that is required to insert a needle deep into the brain without passing through sulci or gyri, which could cause hemorrhaging. The target of the grafts is very specific: It is the nucleus basalis of Meynert, a basal forebrain area that sends cholinergic projections to the hippocampus and cortex. Specially designed needles and anesthesia protocols have been developed for the surgeries, and stereotaxis is used to stabilize the head during the procedure. Whereas early patients received only mild anesthesia—the thinking being that keeping the patient cognizant during surgery would be beneficial—patients are now deeply anesthetized during the surgery to ensure that they do not move.
The eighth and final patient in this Phase I safety study received the NGF implant on November 1. Each pair of patients has received a progressively greater volume of transplanted cells, and the researchers waited two months in between each patient’s surgery. The first two subjects received grafts of a small volume of cells to one side of the brain, while the next two received the same cell volume bilaterally. The fifth and sixth patients received double the volume, and the final two got five times the initial dose. Five women and three men, age 53 to 76, are enrolled.
The team is now following the six patients in whom the surgery did not produce complications. No adverse effects on cognition have been seen, which Tuszynski said is an indication that the genes and vector are safe. The grafts are morphologically similar to those in the primate models on which this trial was based. It is too early to draw any conclusions regarding efficacy. Tuszynski explained that there is evidence the grafts have been innervated by cholinergic axons and presented MRI scans from one patient that indicated a greater uptake of cholinesterase on the side where cells were implanted. The full data set is expected in one year.
Tuszynski concluded that the study indicates that cholinergic neurons can be accurately targeted for NGF grafts, that implanted cells express NGF without adverse effects, and that patients need to be deeply anesthetized. If the pilot is successful, a follow-up trial will likely utilize an in-vivo gene transfer technique (as opposed to this ex-vivo protocol), which was not adequately developed at the start of this trial, but is hypothetically safer because it requires fewer needle passes into the brain. Systems where NGF expression can be regulated are "not yet ready for clinical trial use until immunological issues are sorted out," Tuszynski said.
Brenda Patoine is a science writer in Lagrangeville, New York, who writes for BrainWork and other publications.